1. What Is the Biology of Hair Growth?

Hair is made of a filament protein called keratin that is produced by the hair follicle found in the skin dermis and contains specific stem cells. Hair follicles are dynamic structures that follow a cycle that leads to hair renewal.

This cycle follows a sequence of rapid growth (anagen), regression (catagen), and resting periods (telogen) of about 100 days. Following this sequence, older cells in the follicles are pushed upward to the surface of the skin and replaced by new cells [1]. Although without noticing a difference, we lose about 50-100 hairs per day.

2. What Causes Hair Loss?

A. Illness and Hair Loss

• Telogen Effluvium: This condition is associated with an excessive resting period of the hair renewal process which is related to the telogen phase of the hair growth cycle. Telogen Effluvium is caused by many conditions such as surgery, stress, thyroid disorders, iron deficiency, physical injury, changes in diet and weight loss, and hormonal changes [2].

• Autoimmune diseases (Alopecia Areata): In autoimmune diseases, our immune cells should target foreign invaders such as pathogens, and start attacking hair follicles leading to hair loss [3].

• Fungal infection (Tinea Capitis): Although it mainly affects children, this type of hair loss is caused by dermatophyte fungi that target the scalp leading to large inflammation, pustular plaques, and extensive hair loss [4].

• Thyroid disorders (Hyperthyroidism and hypothyroidism): Both hyperthyroidism and hypothyroidism have been reported to increase the number of telogen hairs [5].

• Sex hormone imbalance: This is also known as androgenic alopecia, where large hair follicles are induced to become smaller by the excessive secretion of the androgen steroid hormone, dihydrotestosterone [6].

B. Weight Loss and Hair Loss

A sudden weight loss associated with decreased protein intake and vitamin B3 deficiency has been associated with acute telogen effluvium. Additionally, associations between weight loss-related nutritional deficiencies, chronic telogen effluvium, androgenetic alopecia (AGA), female pattern hair loss (FPHL), and alopecia areata, have also been reported [7].

C. Stress and Hair Loss

Acute and chronic stress has been reported as an inducer of telogen effluvium. Several stress hormones, such as catecholamines, prolactin, ACTH (Adrenocorticotropic hormone), CRH (corticotropin-releasing hormone), b-endorphins, and glucocorticoids, and neuropeptides such as substance P are directly or indirectly in affecting the function of hair follicles [8].

D. Iron Deficiency and Hair Loss

Iron is a cofactor for ribonucleotide reductase, a rate-limiting enzyme for DNA synthesis. As hair follicle cells are rapidly dividing cells, their need for DNA synthesis increases, and therefore, iron deficiency can reduce the number of hair follicles produced [9].

E. Cancer Treatment and Hair Loss

Cancer cells are highly growing cells and to slow down or block their growth, chemotherapy is used as treatment. Chemotherapeutic compounds intercalate between the DNA of cancer cells which slow down their growth or trigger their cell death. However, as hair follicle cells are also highly growing cells, chemotherapy may also affect their growth [10].

F. Genetics and Hair Loss

An association between genetic variability of the androgen receptor (AR) a genetic predisposition for androgenic alopecia and male-pattern baldness has been reported. Analysis of the AR locus (gene position on the chromosome) on chromosome X (in both males and females), found that polyglycine-encoding GGN repeat is likely responsible [11].

3. What Are the Symptoms of Hair Loss?

Depending on the causes, hair loss can manifest in different ways:

• Age-related gradual thinning on top of the head.
• Circular or patchy bald spots on the scalp.
• Stress- and emotional-induced sudden loosening of hair.
• Full-body hair loss associated with chemotherapy.
• Patches that spread over the scalp are caused by fungal infections.

4. What is the Treatment for Hair Loss?

Most treatments for hair loss are associated with the determination of the underlying causes; however, some require lifestyle changes, while others involve medications.

• Reduce stress If the hair loss has stress-related origins.
• If on the diet for weight loss, it is essential to choose a diet that has enough proteins, vitamins, and iron.
• Hair loss should stop following the end of the chemotherapy.
• In cases where the hair loss is permanent (e.g., surgery, physical injury), life would be much easier if you accept your appearance and live with it.
• For genetic causes of hair loss such as androgenic alopecia and male-pattern baldness, a hair lotion containing minoxidil is used. Male-pattern baldness (men) is also treated with finasteride.
• Other treatment for hair loss involves injection or skin application of steroids, artificial hair transplant, and hair transplant.

Frequently Asked Questions Answers about Why I Am Losing My Hair?

Why am I losing my hair?

Hair loss can be caused by a variety of factors including genetics, hormonal changes, medical conditions, medications, and lifestyle factors.

Is hair loss hereditary?

Yes, hereditary hair loss, also known as androgenetic alopecia, is the most common cause of hair loss and is often passed down through generations.

Can stress cause hair loss?

Yes, stress can trigger hair loss, especially in individuals who are genetically predisposed to it. This type of hair loss is often temporary and can be reversed with stress management techniques.

Are there any medical conditions that can cause hair loss?

Yes, medical conditions such as thyroid disorders, autoimmune diseases, and scalp infections can contribute to hair loss.

Can medications cause hair loss?

Yes, certain medications, such as those used for cancer, arthritis, depression, and heart problems, can cause hair loss as a side effect.

How can I prevent hair loss?

While some causes of hair loss are unavoidable, you can minimize the risk by maintaining a healthy diet, reducing stress, avoiding harsh treatments and styles, and using gentle hair care products.

Is hair loss reversible?

It depends on the cause of the hair loss. Some types of hair loss, such as those caused by stress or certain medications, may be reversible once the underlying cause is addressed.

However, hereditary hair loss may be more challenging to reverse but can often be managed with treatments to slow down the progression.

What treatments are available for hair loss?

Treatment options for hair loss include medications like minoxidil and finasteride, hair transplant surgery, low-level laser therapy, and platelet-rich plasma (PRP) therapy. The most suitable treatment will depend on the cause and severity of your hair loss.

When should I see a doctor about my hair loss?

It’s advisable to see a doctor if you notice sudden or severe hair loss, hair loss accompanied by itching or pain, hair loss at a young age, or if you have other symptoms such as fatigue or weight loss, as these could indicate an underlying medical condition.

Are there any natural remedies for hair loss?

Some people find relief from hair loss with natural remedies such as essential oils, scalp massages, and dietary supplements like biotin and saw palmetto.

However, it’s essential to consult with a healthcare professional before trying any natural remedies to ensure they are safe and effective for you.

Conclusion

Although most hair loss is temporary, losing hair can be extremely stressful as it is part of who we are, and how we look. Most cases of hair loss can be treated, however, other therapeutic approaches exist and are being developed for permanent hair loss.

References

[1] Krause, K. and Foitzik, K., 2006, March. Biology of the hair follicle: the basics. In Seminars in cutaneous medicine and surgery (Vol. 25, No. 1, pp. 2-10).

[2] Malkud, S., 2015. Telogen effluvium: a review. Journal of clinical and diagnostic research: JCDR, 9(9), p.WE01.

[3] Alexis, A.F., Dudda-Subramanya, R. and Sinha, A.A., 2004. Alopecia areata: autoimmune basis of hair loss. European journal of dermatology, 14(6), pp.364-370.

[4] Hay, R.J., 2017. Tinea capitis: current status. Mycopathologia, 182(1), pp.87-93.

[5] Babb-Tarbox, M. and Bergfeld, W.F., 2008. Alopecia and Thyroid Disease. In Thyroid Disorders with Cutaneous Manifestations (pp. 121-143). Springer, London.

[6] Price, V.H., 2003, June. Androgenetic alopecia in women. In Journal of Investigative Dermatology Symposium Proceedings (Vol. 8, No. 1, pp. 24-27). Elsevier.

[7] Guo, E.L. and Katta, R., 2017. Diet and hair loss: effects of nutrient deficiency and supplement use. Dermatology practical & conceptual, 7(1), p.1.

[8] Hadshiew, I.M., Foitzik, K., Arck, P.C. and Paus, R., 2004. Burden of hair loss: stress and the underestimated psychosocial impact of telogen effluvium and androgenetic alopecia. Journal of investigative dermatology, 123(3), pp.455-457.

[9] Kantor, J., Kessler, L.J., Brooks, D.G. and Cotsarelis, G., 2003. Decreased serum ferritin is associated with alopecia in women. Journal of Investigative Dermatology, 121(5), pp.985-988.

[10] Botchkarev, V.A., 2003, June. Molecular mechanisms of chemotherapy-induced hair loss. In Journal of Investigative Dermatology Symposium Proceedings (Vol. 8, No. 1, pp. 72-75). Elsevier.[11] Hillmer, A.M., Hanneken, S., Ritzmann, S., Becker, T., Freudenberg, J., Brockschmidt, F.F., Flaquer, A., Freudenberg-Hua, Y., Abou Jamra, R., Metzen, C. and Heyn, U., 2005. Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia. The American Journal of Human Genetics, 77(1), pp.140-148.

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GDF11 has been proposed as a rejuvenating factor as it was reported that it restores skeletal muscle stem cell function and enhances muscle repair after injury.

In this blog, scientific literature on GDF11 is explored to clarify the potential role of this factor in tissue regeneration and longevity.

I. What Is the Function of GDF11 in the Body?

Before discussing the role of GDF11 in the body, it is important to provide information on its expression in adults and during embryogenesis.

1. Where Is GDF11 Expressed in Humans?

A. Where is GDF11 Expressed in Human Adults?

GDF11In humans, the GDF11 protein is highly expressed in the brain, testis, soft tissue, breast, placenta, prostate, stomach, epididymis, and gallbladder. It is mildly expressed in the intestines, salivary glands, the thyroid, the parathyroid, the adrenal gland, the liver, and the tonsils.

However, it appears that there is no protein expression in the other organs and tissues such as the heart, the skin, skeletal and smooth muscles, or the bone marrow [2].

B. Where is GDF11 Expressed During Human Embryogenesis?

Although based on RNA studies in mice, Gdf11 is mostly expressed in the primitive streak and tailbud regions. The primitive streak is a structure that generates new mesodermal progenitors (stem cells) that migrate and differentiate into the mesoderm germ layer that generates future cells such as cardiac muscle cells, skeletal muscle cells, tubule cells of the kidney, red blood cells, and smooth muscle cells (in the gut).

The Tail bud or caudal cell mass is the embryonic structure that is later responsible for the generation of the lower end of the spinal cord [3].

2. How does GDF11 Function?

As a member of the superfamily of the Transforming Growth Factor beta (TGF-β) and the subfamily of the BMP, GDF11 induces cellular signaling through the canonical (classical) signal transduction pathways involving R-SMADS and SMAD4.

However, GDF11 also induces cellular signaling through non-canonical pathways such as the MAPK (Mitogen-Activated Protein Kinase) pathway. Both signalings require the binding of GDF11 to the activin receptors type II A or B [4].

The activation of the canonical and non-canonical pathways results in the transcriptional induction of the expression of genes that control cell proliferation and differentiation, wound healing, and the immune system [5].

3. How Is GDF11 Activated?

Although little is known about the mechanisms that induce the expression of GDF11, a study showed that histone deacetylase 3 (HDAC3), might be involved. The inhibition of HDAC3 using the drug trichostatin A (TSA) promoted the expression of GDF11 [6].

4. What Is the Role of GDF11 in Regeneration?

Although performed in mice, several studies reported that GDF11 can reverse age-related cardiac hypertrophy, and dysfunction of skeletal muscles, accelerate skin wound healing, improve the neuronal activity in the hippocampus, and enhance angiogenesis by promoting the therapeutic functions of mesenchymal stem cells.

A. Does GDF11 Improve Age-Related Vascular and Neuronal Activity in the Hippocampus?

A study reported that bloodstream delivery of GDF11 to older mice improves vasculature and promotes neurogenesis in the hippocampus. The authors suggest that GDF11 could be used to improve the central nervous system function [7].  

B. Does GDF11 Reverse Age-Related Dysfunction of the Skeletal Muscle?

A study reported that the systemic delivery of GDF11 in older mice reverses functional deficiencies and restores the genomic integrity of muscle stem cells. The authors suggest that systemic delivery of GDF11 could be therapeutically used to reverse age-related skeletal muscle and stem cell dysfunction [8].

C. Does GDF11 Reverse Age-Related Cardiac Hypertrophy?

In aged individuals, heart hypertrophy is frequently associated with heart failure. Using a technique called parabiosis which consists of sharing circulation between younger and older mice with cardiac hypertrophy, a study reported that the hypertrophy was completely reversed in the older mice.

The authors identified GDF11 as the factor responsible and suggested that it could be used in therapy to reverse age-related cardiac hypertrophy [9].

D. Does GDF11 Accelerate Skin Wound Healing?

A study investigated the effects of topically applying truncated GDF11 on wound healing of diabetes mellitus (DM) mice models and reported that truncated GDF11 promotes skin wound healing by stimulating dermal fibrosis. They suggest truncated GDF11 could be used as a potential agent for treating skin wounds in the diabetic population [10].

E. Does GDF11 enhance Angiogenesis?

A study investigated the potential use of GDF11 capacity in inducing proangiogenic activities of mesenchymal stem cells (MSCs) for angiogenic therapy. They found that GDF11 promotes the therapeutic functions of MSCs that could be used for ischemic diseases [11].

II. Frequently Asked Questions about Is GDF11 a Rejuvenating Factor?

What is GDF11?

GDF11, or Growth Differentiation Factor 11, is a protein that belongs to the TGF-β superfamily and plays a role in various cellular processes, including cell growth, differentiation, and regeneration.

How does GDF11 relate to rejuvenation?

Studies have suggested that GDF11 levels decrease with age, and replenishing GDF11 levels in older animals has shown promising results in reversing age-related declines in various tissues and organs, suggesting a potential role in rejuvenation.

What evidence supports the rejuvenating effects of GDF11?

Research conducted on animal models, particularly mice, has demonstrated that restoring GDF11 levels can improve cardiac function, enhance muscle regeneration, and even reverse age-related cognitive decline.

Can GDF11 supplementation reverse aging in humans?

While animal studies have shown promising results, the effectiveness and safety of GDF11 supplementation in humans are still being investigated. Clinical trials are needed to determine its potential as a rejuvenating therapy in humans.

Are there any risks associated with GDF11 supplementation?

The long-term effects and potential risks of GDF11 supplementation in humans are not yet fully understood. Some studies have raised concerns about potential adverse effects, such as promoting tumor growth or exacerbating certain age-related conditions.

How is GDF11 administered for rejuvenation purposes?

In animal studies, GDF11 has been administered via injections or infusion directly into the bloodstream. However, the optimal dosage, frequency, and mode of administration for humans have yet to be determined.

What other factors contribute to aging besides GDF11 levels?

Aging is a complex process influenced by various genetic, environmental, and lifestyle factors. While GDF11 may play a role in certain aspects of aging, addressing other factors such as diet, exercise, and stress management is also important for overall health and longevity.

Is there ongoing research on GDF11 and rejuvenation?

Yes, research on GDF11 and its potential as a rejuvenating factor is ongoing. Scientists continue to investigate its mechanisms of action, potential benefits, and safety profile in both animal models and human clinical trials.

Conclusion

A rejuvenating function of GDF11 has been reported by several studies that involved different organs and tissues. However, all these investigations were performed in mice which may not result in similar outcomes in humans. Therefore, clinical trials using GDF11 would certainly determine if this factor is the “Mythical Fountain of Youth”.

References

[1] Morikawa, M., Derynck, R. and Miyazono, K., 2016. TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology. Cold Spring Harbor Perspectives in Biology, 8(5), p.a021873.

[2] https://www.proteinatlas.org/ENSG00000135414-GDF11/tissue

[3] Suh, J., Eom, J.H., Kim, N.K., Woo, K.M., Baek, J.H., Ryoo, H.M., Lee, S.J. and Lee, Y.S., 2019. Growth differentiation factor 11 locally controls anterior–posterior patterning of the axial skeleton. Journal of cellular physiology, 234(12), pp.23360-23368.

[4] Simoni-Nieves, A., Gerardo-Ramírez, M., Pedraza-Vázquez, G., Chávez-Rodríguez, L., Bucio, L., Souza, V., Miranda-Labra, R.U., Gomez-Quiroz, L.E. and Gutiérrez-Ruiz, M.C., 2019. GDF11 implications in cancer biology and metabolism. Facts and controversies. Frontiers in oncology, 9, p.1039.

[5] Morikawa, M., Derynck, R. and Miyazono, K., 2016. TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology. Cold Spring Harbor Perspectives in Biology, 8(5), p.a021873.

[6] Zhang, X., Wharton, W., Yuan, Z., Tsai, S.C., Olashaw, N. and Seto, E., 2004. Activation of the growth-differentiation factor 11 gene by the histone deacetylase (HDAC) inhibitor trichostatin A and repression by HDAC3. Molecular and cellular biology, 24(12), pp.5106-5118.

[7] Ozek, C., Krolewski, R.C., Buchanan, S.M. and Rubin, L.L., 2018. Growth Differentiation Factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice. Scientific reports, 8(1), pp.1-13.

[8] Sinha, M., Jang, Y.C., Oh, J., Khong, D., Wu, E.Y., Manohar, R., Miller, C., Regalado, S.G., Loffredo, F.S., Pancoast, J.R. and Hirshman, M.F., 2014. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science, 344(6184), pp.649-652.

[9] Loffredo, F.S., Steinhauser, M.L., Jay, S.M., Gannon, J., Pancoast, J.R., Yalamanchi, P., Sinha, M., Dall’Osso, C., Khong, D., Shadrach, J.L. and Miller, C.M., 2013. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell, 153(4), pp.828-839.

[10] Li, Q., Jiao, L., Shao, Y., Li, M., Gong, M., Zhang, Y., Tan, Z., Wang, Y., Yang, X., Wang, Z. and Zhang, Y., 2020. Topical GDF11 accelerates skin wound healing in both type 1 and 2 diabetic mouse models. Biochemical and biophysical research communications, 529(1), pp.7-14.

[11] Zhang, C., Lin, Y., Zhang, K., Meng, L., Hu, X., Chen, J., Zhu, W. and Yu, H., 2021. GDF11 enhances therapeutic functions of mesenchymal stem cells for angiogenesis. Stem Cell Research & Therapy, 12(1), pp.1-17.

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Although most of the cells progress to generate different tissues and organs, few cells conserve stem cell-like characteristics that are committed to the continuous maintenance and repair of tissues and organs throughout the life of an individual [1]. These cells are known as adult stem cells or adult tissue-specific stem cells which exhaustion occurs during aging [2].

What is Stem Cell Exhaustion?

Within tissues and organs of the body, populations of stem cell-like cells known as adult stem cells or adult tissue-specific stem cells maintain and repair tissues and organs throughout the life of an individual.

However, as we age, these populations of cells start to deplete due to several causes that can act individually or collectively such as DNA damage, proteostasis, epigenetics, telomere shortening, mitochondria dysfunction, and cellular senescence [2].

1- What is the Link Between DNA damage and Stem Cell Exhaustion?

During their lifetime within tissues and organs, adult stem cells are the target of genotoxic effects that lead to DNA mutations which result in their functional inactivation or death. These events are enhanced with time and are more pronounced at old age due to the decreased activity of the DNA repair machinery within the cells [3].

2- What is the Link Between the Loss of Proteostasis and Stem Cell Exhaustion?

As products of DNA transcription and RNA translation, proteins are molecules that are involved in all functional activities within the cells. However, when proteins are generated, they must pass a quality control test that relies on checking their synthesis, folding, and degradation. This process is known as protein homeostasis or proteostasis.

Unfortunately, this process is also affected with age leading to abnormal folding, toxic aggregation, and accumulation of damaged proteins, that result in cellular damage and tissue dysfunction [4].

3- What is the Link Between Epigenetics and Stem Cell Exhaustion?

During the process of aging, DNA is subject to epigenetic changes such as acetylation and methylation that control the expression of genes that control longevity. For example, an increase in methylation of lineage-specific gene expression was associated with decreased self-renewal of hematopoietic stem cells (HSCs) [5].

4- What is the Link Between Telomere Shortening and Stem Cell Exhaustion?

During aging, a shortening of telomeres-specialized chromatin structures that are found at the end of chromosomes leads to gene erosion and chromosomal aberrations that result in functional inactivation, death, or senescence of stem cells. A study demonstrated an association between longer telomeres and functional stem cells in hair follicles, intestines, testis, cornea, and the brain [6].  

5- What is the Link Between Mitochondria Dysfunction and Stem Cell Exhaustion?

Reactive oxygen species (ROS) that are produced by the mitochondria can induce oxidative damage to the mitochondria’s functions. A theory proposed that elevated ROS are associated with a decline in the integrity of mitochondria [7].

This possibility was tested by a study that showed that hematopoietic stem cells that lack the gene encoding the mitochondrial antioxidant enzyme, superoxide dismutase 2, have oxidative stress-mediated hematopoietic abnormalities [8].

6- What is the Link Between Cellular Senescence and Stem Cell Exhaustion?

Cellular senescence is associated with cells that stopped dividing without entering a programmed cell death. This cellular arrest in growth is associated with DNA damage and/or shortening of the telomeres in senescent cells. A loss of the stem cell pool may be due to a percentage of adult stem cells entering into senescence during aging [9].

How is Stem Cell Exhaustion Slowed down?

To slow down stem cell exhaustion, changes in lifestyle, such as exercise and appropriate diet, can significantly delay this process. Other means are intensively investigated by researchers such as the development of medications that delay stem cell exhaustion and regenerative medicine.

1- How does Lifestyle Slowdown Stem Cell Exhaustion?

Lifestyle changes in diet and exercise were demonstrated to promote longevity.

How Diet Slows Down Stem Cell Exhaustion?

Dietary interventions, including calorie restriction, dietary restriction, protein restriction, and epigenetic diet, promote longevity [10]. Calorie restriction was shown to promote the frequency and function of skeletal muscle stem cells and reduce the severity of aging and aging-related diseases [11][12].

How does Exercise Slow Down Stem Cell Exhaustion?

Several studies demonstrated that exercise promotes the survival and proliferation of stem cells. For example, exercise has been shown to increase the size of the hippocampus in human adults [6], and in rodent models, it has been shown to increase the proliferation and survival of the progenitor cells as they differentiated and matured into granule neurons in the dentate gyrus (DG) [13] [14].

2- How do NAD⁺ Precursors Slowdown Stem Cell Exhaustion?

Nicotinamide adenine dinucleotide (NAD⁺) is an essential mitochondrial cofactor in the redox pathway that contributes to the generation of ATP. When NAD⁺ is in the nucleus, it promotes the balance between nuclear and mitochondria encoded respiratory chain subunits.

In a model of aged mice and Drosophila, a decline in nuclear NAD⁺ was reported to disrupt oxidative phosphorylation leading to mitochondria dysfunction suggesting a potential role of nuclear NAD⁺ in the maintenance of the stem cell pool [15].

3- How does Rapamycin Slowdown Stem Cell Exhaustion?

Rapamycin is a bacterial compound that has immunosuppressant activities towards T and B cells. Rapamycin has been reported to restore the self-renewal and hematopoietic potential of aged hematopoietic stem cells through the inhibition of the mTOR pathway. The inhibition of this pathway results in increased glycolysis and removal of dysfunctional proteins by autophagy [16].

4- How do Senolytics Slowdown Stem Cell Exhaustion?

To eradicate senescent cells from the body and restore the dysfunction of stem cells, several drugs have been developed such as Dasatinib, Quercetin, Fisetin, and Navitoclax. Although the exact mechanism of action is not provided, these drugs appear to act by inactivating anti‐apoptotic pathways [17].

5- How Can Regenerative Medicine Slowdown Stem Cell Exhaustion?

Regenerative medicine is a therapeutic medical field that focuses on developing technologies that use stem cells to replace, engineer, or regenerate human or animal cells, tissues, or organs to restore or establish normal function [18].

Although this approach encounters many technical challenges, non-embryonic and mature cells can be reprogrammed back into stem cells using cloning methods that promote the expression of a core of transcriptional network involving cell factors such as OCT4, SOX2, KLF4, and C-Myc [1]. These reprogrammed cells can then be differentiated into tissue-specific stem cells before transplantation into patients.

Conclusion

During aging, stem cell exhaustion is due to several causes that can act individually or collectively such as DNA damage, proteostasis, epigenetics, telomere shortening, mitochondria dysfunction, and cellular senescence.

However, many studies on aging and longevity indicate the importance of diet and exercise in these processes and future medical advances will certainly contribute to this effort in preventing or slowing down aging.

References

[1] Regad, T., Sayers, T. and Rees, R., 2015. Principles of stem cell biology and cancer: future applications and therapeutics. John Wiley & Sons.

[2] Oh, J., Lee, Y.D. and Wagers, A.J., 2014. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nature medicine, 20(8), pp.870-880.

[3] Rossi, D.J., Bryder, D., Seita, J., Nussenzweig, A., Hoeijmakers, J. and Weissman, I.L., 2007. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature, 447(7145), pp.725-729.

[4] Bucciantini, M., Giannoni, E., Chiti, F., Baroni, F., Formigli, L., Zurdo, J., Taddei, N., Ramponi, G., Dobson, C.M. and Stefani, M., 2002. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. nature, 416(6880), pp.507-511.

[5] Beerman, I., Bock, C., Garrison, B.S., Smith, Z.D., Gu, H., Meissner, A. and Rossi, D.J., 2013. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell stem cell, 12(4), pp.413-425.

[6] Flores, I., Canela, A., Vera, E., Tejera, A., Cotsarelis, G. and Blasco, M.A., 2008. The longest telomeres: a general signature of adult stem cell compartments. Genes & development, 22(5), pp.654-667.

[7] Harman, D., 1972. Free radical theory of aging: dietary implications. The American journal of clinical nutrition, 25(8), pp.839-843.

[8] Ahmad, K.A., CLEMENT, M.V. and Pervaiz, S., 2003. Pro‐oxidant Activity of Low Doses of Resveratrol Inhibits Hydrogen Peroxide—Induced Apoptosis. Annals of the New York Academy of Sciences, 1010(1), pp.365-373.

[9] Geiger, H., De Haan, G. and Florian, M.C., 2013. The ageing haematopoietic stem cell compartment. Nature Reviews Immunology, 13(5), pp.376-389.

[10] Kitada, M., Ogura, Y., Monno, I. and Koya, D., 2019. The impact of dietary protein intake on longevity and metabolic health. EBioMedicine, 43, pp.632-640.

[11] Cerletti, M., Jang, Y.C., Finley, L.W., Haigis, M.C. and Wagers, A.J., 2012. Short-term calorie restriction enhances skeletal muscle stem cell function. Cell stem cell, 10(5), pp.515-519.

[12] Piper, M.D. and Bartke, A., 2008. Diet and aging. Cell metabolism, 8(2), pp.99-104.

[13] Seri, B., Garcıa-Verdugo, J.M., McEwen, B.S. and Alvarez-Buylla, A., 2001. Astrocytes give rise to new neurons in the adult mammalian hippocampus. Journal of Neuroscience, 21(18), pp.7153-7160.

[14] Kim, K., Sung, Y.H., Seo, J.H., Lee, S.W., Lim, B.V., Lee, C.Y. and Chung, Y.R., 2015. Effects of treadmill exercise-intensity on short-term memory in the rats born of the lipopolysaccharide-exposed maternal rats. Journal of exercise rehabilitation, 11(6), p.296.

[15] Gomes, A.P., Price, N.L., Ling, A.J., Moslehi, J.J., Montgomery, M.K., Rajman, L., White, J.P., Teodoro, J.S., Wrann, C.D., Hubbard, B.P. and Mercken, E.M., 2013. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell, 155(7), pp.1624-1638.

[16] Chen, C., Liu, Y., Liu, Y. and Zheng, P., 2009. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Science signaling, 2(98), pp.ra75-ra75.

[17] Kirkland, J.L. and Tchkonia, T., 2020. Senolytic drugs: From discovery to translation. Journal of internal medicine, 288(5), pp.518-536.

[18] Atala, A., Lanza, R., Mikos, T. and Nerem, R. eds., 2018. Principles of regenerative medicine. Academic press.

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They have the specific characteristics of self-renewal and generate differentiated and specialized cells that contribute to tissue homeostasis and regeneration following injuries or diseases. They are found in several organs including the brain, liver, bone marrow, eyes, gut, skin, and muscle [1].

1. Origin of Adult Stem Cells

To better understand how and where adult stem cells originated, it is important to discuss early embryonic development. Following the fecundation of an egg by a sperm, the fertilized egg begins a series of cell divisions that lead to the formation of a mass of cells known as the blastula.

This mass contains two types of cell masses, the trophoblast, and the inner cell mass. The trophoblast leads to the formation of the placenta and the inner cell mass to the formation of an embryo [2].

Before the generation of a fully developed embryo, the inner cell mass, composed of embryonic stem cells, will generate three types of tissues known as domains: the endoderm, the mesoderm, and the ectoderm.

At this stage of development, unlike the embryonic stem cells that can generate any type of cells, stem cells that are found in these domains are committed to the generation of tissues that are specific for each domain.

For instance, the endoderm, also known as the internal layer, generates lung cells (alveolar cells), thyroid cells, and digestive cells (pancreatic cells).

The mesoderm will generate cardiac muscle cells, skeletal muscle cells, tubule cells of the kidney, red blood cells, and smooth muscle cells (in the gut). The ectoderm will generate the skin cells of the epidermis, pigment cells, and neurons of the brain [3].

Finally, although most of the cells progress to generate different tissues and organs, few cells conserve stem cell-like characteristics that are committed to the continuous maintenance and repair of tissues and organs throughout the life of an individual. These cells are known as adult stem cells or adult tissue-specific stem cells.

2. Adult Stem Cells of the Bone Marrow

The bone marrow is the niche of hematopoietic stem cells (HSCs) that generate cells of the blood that contribute to the transport of nutrients and oxygen, coagulation, and immunity. HSCs produce two types of progenitor cells: myeloid progenitors and lymphoid progenitors.

The myeloid progenitors generate erythrocytes (red blood cells), platelets for coagulation, and myeloblasts that produce basophil, eosinophil, neutrophil, and monocytes that contribute to immunity. Lymphoid progenitors produce lymphocytes T and lymphocytes B which are also key players in immunity [4].

3. Brain Adult Stem Cells

Adult neural stem cells are found in the hippocampal dentate gyrus (DG) and the brain subventricular zone (SVZ). Hippocampal neural stem cells generate hippocampal neurons named granule neurons of the dentate gyrus (DG) that are essential to memory function [5].

The subventricular adult neural stem cells generate neuroblast precursors of interneurons that migrate to the olfactory bulb, a neural structure involved in receiving sensations of smell and discriminating between different odors [6].

4. Intestinal Adult Stem Cells

In the small intestine and colon, adult stem cells are located at the base of the crypts, which are protrusions of the gut wall that project into the gut lumen and contribute to the transport of absorbed nutrients into the body.

These stem cells contribute to the renewal and function of the gut epithelium through the generation of enterocytes, goblet cells, tuft cells, Paneth cells, and microfold cells [7].

The enterocytes contribute to the gut absorption of nutrients, the goblet cells secrete mucus and hormones, the tuft cells play a role in nutrient sensing, Paneth cells secrete anti-bacterial products, and the microfold cells play a role in mucosal immunity.

5. Adult Stem Cells of the Skin

The skin adult stem cells are found in the epidermis of the skin where they contribute to the maintenance of tissue homeostasis, hair regeneration, and epidermis repair after injury.

They are located at the base of the epidermis within a niche known as the epidermal proliferative unit (EPU). Within the EPU, inner cells differentiate and move outward to continually replace the cells at the surface of the skin [8].

6. Liver Adult Stem Cells

Following hepatectomy, chemical injury, or diseases, the liver can regenerate suggesting the presence of liver stem cells that can produce new liver cells. However, the existence of these cells is controversial as other studies suggested that the generation of new cells is performed by normal liver cells called hepatocytes [9].

It has been shown that hepatocytes are also able to proliferate and generate new liver cells. Nonetheless, other studies demonstrated the presence of liver stem cells within the liver, indicating that both hepatocytes and liver stem cells are involved in liver regeneration [10].

7. Adult Stem Cells of the Eyes

The eye is composed of the cornea, the retina, the lens, the optic nerve, and the retinal pigment epithelium. Studies have shown the presence of stem cells within the retina named Müller cells. These cells play a vital role in maintaining and repairing the eye during physiological conditions [11].

However, other studies have suggested the presence of other types of stem cells such as corneal epithelial cells, and retinal pigment epithelial (RPE) cells [11].

8. Muscle Adult Stem Cells

Within muscles, a population of stem cells known as satellite stem cells, have the potential to regenerate and repair muscles, cartilage, and bones. They are found between the muscle fiber and the basal lamina.

Satellite stem cells can differentiate into myocytes to produce muscle cells, osteoblasts to produce bone tissue, chondroblasts to produce cartilage tissue and adipocytes.

9. Frequently Asked Questions about What Are Human Adult Stem Cells?

What are human adult stem cells?

Human adult stem cells are a type of undifferentiated cell found among differentiated cells in a tissue or organ. They can renew themselves through cell division and can differentiate to yield specialized cell types.

Where are adult stem cells found in the human body?

Adult stem cells are found in various tissues and organs throughout the body, including the bone marrow, brain, skin, liver, skeletal muscles, and blood vessels.

What is the difference between adult stem cells and embryonic stem cells?

Adult stem cells are multipotent, meaning they can differentiate into a limited range of cell types specific to the tissue or organ where they are found. Embryonic stem cells, on the other hand, are pluripotent and have the potential to differentiate into any cell type in the body.

What are the potential applications of adult stem cells in medicine?

Adult stem cells hold promise for regenerative medicine, including treating various diseases and injuries by replacing damaged or diseased cells with healthy ones. They are also studied for their potential in drug discovery and understanding of disease mechanisms.

How are adult stem cells collected for research or medical purposes?

Adult stem cells can be collected from various sources, such as bone marrow aspiration, adipose tissue (fat) extraction, blood draw, and certain tissues during surgery. The collection method depends on the specific type of stem cell and its intended use.

Can adult stem cells be used for treating diseases?

Yes, adult stem cells have been used in clinical trials to treat a range of diseases, including blood disorders, autoimmune diseases, and certain types of cancer. However, further research is needed to fully understand their potential and refine treatment protocols.

Are there any ethical concerns associated with the use of adult stem cells?

Unlike embryonic stem cells, the use of adult stem cells typically does not raise ethical concerns related to embryo destruction.

However, ethical considerations may arise regarding the collection, storage, and use of adult stem cells, especially in the context of informed consent and patient privacy.

How do adult stem cells contribute to tissue repair and regeneration?

Adult stem cells play a crucial role in tissue homeostasis, repair, and regeneration by replenishing damaged or dying cells and promoting tissue renewal.

They can migrate to sites of injury or disease, differentiate into specialized cell types, and release signaling molecules that regulate the healing process.

Conclusion

Adult stem cells are tissue-committed stem cells that play a critical role in tissue homeostasis, repair, and regeneration in physiological and pathological conditions. These cells are also being used in stem cell research and in clinical applications such as in bone marrow or liver transplantation.

References

[1] Regad, T., Sayers, T. and Rees, R., 2015. Principles of stem cell biology and cancer: future applications and therapeutics. John Wiley & Sons.

[2] Moore, K.L., Persaud, T.V.N. and Torchia, M.G., 2018. The developing human-e-book: clinically oriented embryology. Elsevier Health Sciences.

[3] Young, H.E. and Black Jr, A.C., 2004. Adult stem cells. The Anatomical Record Part A: Discoveries in Molecular, Cellular, and Evolutionary Biology: An Official Publication of the American Association of Anatomists, 276(1), pp.75-102.

[4] Seita, J. and Weissman, I.L., 2010. Hematopoietic stem cell: self‐renewal versus differentiation. Wiley Interdisciplinary Reviews: Systems Biology and Medicine, 2(6), pp.640-653.

[5] GoodSmith, D., Chen, X., Wang, C., Kim, S.H., Song, H., Burgalossi, A., Christian, K.M. and Knierim, J.J., 2017. Spatial representations of granule cells and mossy cells of the dentate gyrus. Neuron, 93(3), pp.677-690.

[6] Alvarez-Buylla, A. and Garcıa-Verdugo, J.M., 2002. Neurogenesis in adult subventricular zone. Journal of Neuroscience, 22(3), pp.629-634.

[7] Clevers, H., 2013. The intestinal crypt, a prototype stem cell compartment. Cell, 154(2), pp.274-284.

[8] Potten, C.S., 1974. The epidermal proliferative unit: the possible role of the central basal cell. Cell Proliferation, 7(1), pp.77-88.

[9] He, L., Pu, W., Liu, X., Zhang, Z., Han, M., Li, Y., Huang, X., Han, X., Li, Y., Liu, K. and Shi, M., 2021. Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair. Science, 371(6532).

[10] Herrera, M.B., Bruno, S., Buttiglieri, S., Tetta, C., Gatti, S., Deregibus, M.C., Bussolati, B. and Camussi, G., 2006. Isolation and characterization of a stem cell population from adult human liver. Stem cells, 24(12), pp.2840-2850.

[11] Huang, C., Albon, J., Ljubimov, A.V. and Grant, M.B., 2020. Stem cells in the eye. In Principles of Tissue Engineering (pp. 1115-1133). Academic Press.

[12] Montano, M., 2014. Translational biology in medicine. Elsevier.

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This unique intercellular communication mechanism holds immense potential in understanding various aspects of cellular function, health, and disease progression.

In this article, we delve into the intricacies of Intercellular Mitochondrial Transfer, exploring its mechanisms, biological significance, and potential applications in both research and clinical settings.

I. Understanding Intercellular Mitochondrial Transfer

A. Definition and Concept of IMT

Intercellular Mitochondrial Transfer (IMT) is a dynamic cellular process central to intercellular communication, where mitochondria, the vital energy-producing organelles, are exchanged between adjacent or distant cells.

This phenomenon plays a pivotal role in maintaining cellular homeostasis and responding to various physiological and pathological conditions.

B. Mechanisms of IMT

1. Tunneling Nanotubes (TNTs)

Tunneling nanotubes (TNTs) serve as conduits for the transfer of cellular components, including mitochondria, between neighboring cells. These fine, filamentous structures facilitate direct cytoplasmic connections, enabling efficient transport of mitochondria across cellular boundaries.

2. Extracellular Vesicles (EVs)

Extracellular vesicles (EVs), such as exosomes and microvesicles, represent another mechanism for intercellular mitochondrial transfer.

These membrane-bound vesicles contain a cargo of biomolecules, including mitochondria, which can be released into the extracellular environment and taken up by recipient cells, facilitating mitochondrial exchange.

3. Other Potential Mechanisms

Beyond TNTs and EVs, emerging research suggests the involvement of additional mechanisms in facilitating IMT.

These may include cell-cell fusion events, where mitochondria are exchanged during the fusion of plasma membranes, as well as other forms of intercellular communication pathways yet to be fully elucidated.

Further exploration of these mechanisms promises to uncover the full spectrum of IMT dynamics.

II. Biological Significance of IMT

A. Role of IMT in Cellular Health and Function

Intercellular Mitochondrial Transfer (IMT) plays a crucial role in maintaining cellular health and function by ensuring optimal mitochondrial dynamics within tissues and organs.

Mitochondria are essential for generating energy, regulating cell metabolism, and orchestrating various cellular processes. Through IMT, cells can replenish damaged or dysfunctional mitochondria, thereby preserving cellular viability and functionality.

This process contributes to overall tissue homeostasis and supports cellular adaptation to changing environmental conditions.

B. Implications for Disease Pathology

1. Neurodegenerative Diseases

IMT has emerged as a significant player in the pathogenesis of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s disease. Dysfunctional mitochondria and impaired energy metabolism are hallmark features of these disorders.

IMT offers a mechanism for neuronal cells to exchange healthy mitochondria, potentially mitigating mitochondrial dysfunction and neuronal degeneration.

Understanding the dynamics of IMT in neurodegenerative diseases holds promise for developing novel therapeutic strategies to halt or slow disease progression.

2. Cancer

In cancer biology, IMT has garnered attention for its role in tumor progression and therapeutic resistance.

Cancer cells exhibit altered mitochondrial function and metabolism to sustain their rapid growth and survival. IMT can facilitate the transfer of healthy mitochondria from neighboring stromal or immune cells to cancer cells, promoting their growth and metastatic potential.

Targeting IMT pathways presents a promising avenue for disrupting tumor-stromal interactions and overcoming therapeutic resistance in cancer treatment.

3. Metabolic Disorders

Metabolic disorders, such as diabetes and obesity, are characterized by dysregulated energy metabolism and mitochondrial dysfunction.

IMT may contribute to the pathophysiology of these disorders by modulating mitochondrial bioenergetics and metabolic signaling pathways.

Understanding how IMT influences metabolic homeostasis offers potential therapeutic avenues for managing metabolic diseases and improving patient outcomes.

III. Research and Clinical Applications

A. Current Research Findings on IMT

Recent research efforts have shed light on the intricate mechanisms and functional implications of Intercellular Mitochondrial Transfer (IMT) in various biological contexts.

Studies have elucidated the role of IMT in cellular communication, tissue homeostasis, and disease pathology.

Advanced imaging techniques and molecular tools have enabled researchers to visualize and manipulate IMT dynamics in real time, providing valuable insights into its physiological and pathological significance.

Moreover, investigations into the molecular players involved in IMT have identified potential therapeutic targets for modulating this process in health and disease.

B. Potential Therapeutic Applications

1. Regenerative Medicine

IMT holds immense promise as a therapeutic strategy in regenerative medicine and tissue engineering. By harnessing the capacity of cells to exchange mitochondria, researchers aim to enhance tissue repair and regeneration following injury or disease.

IMT-based approaches may facilitate the delivery of healthy mitochondria to damaged or diseased tissues, promoting cellular recovery and functional restoration.

Furthermore, the transplantation of mitochondria-rich cells or extracellular vesicles containing mitochondria represents a potential avenue for enhancing the efficacy of regenerative therapies in clinical settings.

2. Targeted Drug Delivery

In the realm of targeted drug delivery, IMT offers a novel strategy for delivering therapeutic payloads to specific cell types or tissues.

By engineering donor cells to selectively transfer drug-loaded mitochondria to target cells, researchers can enhance the precision and efficacy of drug delivery systems.

This approach minimizes off-target effects and maximizes therapeutic outcomes while overcoming biological barriers to drug delivery.

Moreover, IMT-mediated drug delivery may enable the circumvention of multidrug resistance mechanisms in cancer cells, thereby improving the effectiveness of anticancer therapies.

IV. Challenges and Future Directions

A. Limitations of Current Research

Despite significant advancements, research on Intercellular Mitochondrial Transfer (IMT) faces several limitations that hinder a comprehensive understanding of this phenomenon.

One major challenge is the complexity of IMT dynamics, which involve multiple cellular mechanisms and regulatory pathways.

Current research techniques may lack the resolution or sensitivity required to fully elucidate the intricacies of IMT, leading to gaps in knowledge regarding its regulation and functional consequences.

Additionally, experimental models used to study IMT may not fully recapitulate the physiological conditions present in vivo, limiting the translatability of research findings to clinical settings.

Overcoming these limitations requires the development of innovative research tools and methodologies that can capture the nuances of IMT dynamics in physiologically relevant contexts.

B. Future Avenues for Exploration

1. Enhanced Imaging Techniques

Advancements in imaging technologies hold great potential for advancing our understanding of IMT dynamics.

High-resolution live-cell imaging techniques, such as super-resolution microscopy and single-molecule imaging, enable researchers to visualize IMT processes with unprecedented detail and precision.

Moreover, the development of genetically encoded fluorescent probes and biosensors allows for real-time monitoring of mitochondrial dynamics within living cells.

By harnessing these cutting-edge imaging tools, researchers can unravel the spatiotemporal dynamics of IMT and gain insights into its functional implications in health and disease.

2. Targeted Manipulation of IMT

Manipulating IMT pathways represents a promising strategy for therapeutic intervention in various disease contexts.

Future research efforts may focus on identifying specific molecular targets involved in regulating IMT and developing pharmacological agents or genetic tools to modulate these pathways.

Additionally, engineering approaches that enable the selective transfer of mitochondria to target cells or tissues hold the potential for enhancing the efficacy of IMT-based therapies.

By precisely controlling IMT processes, researchers can harness its therapeutic potential for treating a wide range of diseases, including neurodegenerative disorders, cancer, and metabolic diseases.

V. Frequently Asked Questions about Intercellular Mitochondrial Transfer

What is Intercellular Mitochondrial Transfer (IMT)?

Intercellular Mitochondrial Transfer (IMT) is a cellular process where mitochondria, the energy-producing organelles, are exchanged between neighboring or distant cells. This phenomenon plays a crucial role in cellular communication and maintaining tissue homeostasis.

What are the mechanisms of Intercellular Mitochondrial Transfer?

IMT can occur through various mechanisms, including tunneling nanotubes (TNTs), extracellular vesicles (EVs), and potentially other pathways.

Tunneling nanotubes are thin, filamentous structures that facilitate direct cytoplasmic connections between cells, allowing for the transfer of mitochondria.

Extracellular vesicles, such as exosomes and microvesicles, also play a role in IMT by transporting mitochondria enclosed within their membrane-bound compartments.

What is the significance of Intercellular Mitochondrial Transfer in health and disease?

IMT is essential for maintaining cellular health and function by replenishing damaged or dysfunctional mitochondria and supporting cellular metabolism.

Dysregulation of IMT has been implicated in various diseases, including neurodegenerative disorders, cancer, and metabolic diseases, highlighting its significance in disease pathology.

How is Intercellular Mitochondrial Transfer studied in research?

Researchers use a combination of imaging techniques, molecular biology tools, and cell culture models to study IMT.

Live-cell imaging allows for the visualization of IMT dynamics in real-time, while genetic manipulation techniques enable researchers to modulate IMT pathways and study their functional consequences.

What are the potential therapeutic applications of Intercellular Mitochondrial Transfer?

IMT holds promise for various therapeutic applications, including regenerative medicine and targeted drug delivery.

By harnessing IMT pathways, researchers aim to develop innovative strategies for repairing damaged tissues, treating neurodegenerative diseases, overcoming drug resistance in cancer, and managing metabolic disorders.

What are the challenges in understanding Intercellular Mitochondrial Transfer?

Challenges in IMT research include deciphering the complex mechanisms underlying IMT, overcoming limitations of current research techniques, and developing clinically relevant models for studying IMT in disease contexts.

Additionally, ensuring the safety and efficacy of IMT-based therapies remains a critical consideration for translational research.

Conclusion

Intercellular Mitochondrial Transfer (IMT) emerges as a fascinating cellular phenomenon with profound implications for both health and disease.

Through intricate mechanisms like tunneling nanotubes and extracellular vesicles, IMT facilitates the exchange of mitochondria between cells, crucial for maintaining cellular function and responding to physiological challenges.

As research continues to unravel the complexities of IMT, its therapeutic potential in regenerative medicine, targeted drug delivery, and disease intervention becomes increasingly evident.

By harnessing the power of IMT, scientists aim to pave the way for innovative treatments that address a wide range of medical conditions, ultimately improving the lives of patients worldwide.

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The mutations can affect embryonic stem cells, leading to teratomas or adult stem cells resulting in tissues specific cancers.

Cancer stem cells are a primary barrier for successful cancer therapy due to their role in the resistance to cancer and in cancer relapse which accounts for approximatively 90% of cancer-related deaths [1].

I. What Is Chemotherapy?

For the treatment of cancer, chemical compounds are used to target the DNA of cancer cells to induce their death.

Due to the high rate of division of cancer cells, chemotherapy can easily attach to the DNA of cancer cells and induce breakages or block their metabolism which results in the activation of the death program within the cancer cells to get rid of them [1].

Unfortunately, chemotherapy can lead to chemotherapy side effects on normal cells that have a high rate of division, such as hair follicle cells, which leads to hair loss.

Therefore, the aim of any chemotherapy is to kill cancer cells with a minimum toxic effect on normal cells.

II. What Are the Types of Chemotherapy?

They are different types of chemotherapy that are grouped into alkylating agents, antimetabolites, plant alkaloids, and antitumor antibiotics [2].

1- What Are Alkylating Agents?

Alkylating agents are the most used chemotherapy drugs. They are compounds that attach to the DNA of cancer cells to cause breakages (damages) which stop the cancer cells from dividing, and therefore, trigger their death.

Among the alkylating agents used for chemotherapy are cisplatin, cyclophosphamide, chlorambucil, busulfan, lomustine, semustine, carmustine, thiotepa, and dacarbazine.

2- What Are Antimetabolites?

Antimetabolites are compounds that are used to “trick” enzymes of cancer cells to consume and use as nutrients for their enzymatic reactions.

They are meant to replace normal nutrients with inefficient ones (antimetabolites) to starve the cancer cells leading to their death.

Examples of antimetabolites that are used in chemotherapy include methotrexate, 6-mercaptopurine; 5-fluorouracil, fludarabine, gemcitabine, pemetrexed, and cytarabine.

3- What Are Plant Alkaloids?

These drugs are chemicals naturally produced by plants and act specifically on the division cycle of cancer cells (cell cycle).

Among the plant alkaloids agents used for chemotherapy are doxorubicin, actinomycin D, and mitomycin.

4- What Are Antitumor Antibiotics?

The DNA of cells, including cancer cells, is packed in the nucleus in a form of structures known as nucleosomes. For the DNA (and therefore genes) to be able to express a messenger RNA for proteins synthesis, nucleosomes must open.

Antitumor antibiotics prevent the opening of the nucleosomes, which prevents gene expression and protein synthesis necessary for the survival of cancer cells.

Examples of antitumor antibiotics that are used in chemotherapy include anthracyclines (e.g., epirubicin, doxorubicin, daunorubicin, mitoxantrone, and idarubicin), actinomycins (e.g., plicamycin and dactinomycin), bleomycin, and mitomycin.

III. How Do Cancer Stem Cells Resist Chemotherapy?

Cancer stem cells (CSCs) are associated with the presence of cancer-related mechanisms that allow them to resist cancer therapies, and therefore, contribute to a tumor being aggressive [1].

1- Dormancy

Cancer stem cells can stop dividing and enter a dormancy state which limits the effect of chemotherapeutic compounds that target highly dividing cells.

2- The ATP-binding cassette family of transporters

Cancer stem cells express on their surface molecules such as the ATP-binding cassette family of transporters (e.g., ABCG2) that pump out chemotherapy compounds out of cells which limits their effects.

3- Detoxification

They have elevated levels of ALDH1 (Aldehyde Dehydrogenase) enzymatic activity. This enzyme breakdown chemotherapy compounds and make them inactive, and therefore, provides cancer stem cells with resistance to chemotherapy.

4- Resistance to Cell Death

Within the cells, there are molecules that control the balance between the survival of a cell and its death.

Cancer stem cells have high expression of the pro-survival BCL-2 protein family members that bind to the pro-apoptotic proteins BCL2-associated-X-protein (BAX) and BCL-2 homologous antagonist killer (BAK) and impair their ability to release cell death signals from the mitochondria.

5-Resistance to DNA Damage

Cancer stem cells have a high DNA damage response and repair which allows them to resist damages that are caused by chemotherapy compounds.

6- The Tumor Microenvironment (TME)

The TME or tumor niche is a highly diverse complex that contains cells such as stromal cells, immune cells, epithelial cells, and a network of extracellular macromolecules.

This complex provides support for cancer stem cells within the extracellular matrix (EC) and plays a key role in promoting their progression into a more malignant and chemotherapy-resistant phenotype.

IV. How Do Cancer Stem Cells Cause Relapse?

Cancer stem cells lead to a more aggressive type of tumors probably due to the emergence of highly selective and chemotherapy-resistant clones of cancer stem cells.

Following chemotherapy, the tumors may disappear, however, after a period, which can last years, a more aggressive and resistant cancer may reappear.

Unfortunately, when this happens, the relapsed cancer is mostly made of resistant cancer cells which makes chemotherapy a difficult choice for treatments.

V. How Is Resistance to Chemotherapy Treated?

Although several drugs are being tested in clinical trials, success has been limited for some drugs due to their toxicity or lack of response [3].

Treatment of advanced cholangiocarcinoma, using CAR-T technology (antibody-based technology) led to toxicity.

Treatment of refractory acute myeloid leukemia metastatic colorectal cancer using monoclonal antibodies led to either limited responses to the therapy or toxicity.

However, other drugs are still being tested in the clinic and the outcome will be known in the future.

Various types of tumors and hematological malignancies are being treated with different types of monoclonal antibodies but the results are not yet available.

A clinical trial that uses a vaccine for the treatment of glioblastoma multiforme has not yet been published.

Conclusion

To prevent resistance and relapse associated with cancer stem cells in patients suffering from aggressive cancers, scientists are investigating the possibility of combining traditional chemotherapy with other types of therapies, such as monoclonal antibodies, and CAR-T technology.

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I. Do Regenerative Medicine Use Embryonic Stem Cells?

To generate new cells, tissues and organs, this technology may rely on the use of embryonic stem cells (ES cells) that must be obtained from early developed embryos. However, this approach is highly controversial due to the ethical issues surrounding the use of embryos.

II. What are the Other Approaches to Obtain Stem Cells for Regenerative Medicine?

1- Induced pluripotent stem cells

To avoid ethical issues surrounding the use of embryos for the obtention of stem cells, researchers developed a different method that relies on cell reprogramming.

In this method, non-embryonic and mature cells (Somatic cells) are reprogrammed into stem cells using cloning methods that consist in promoting the expression of stem cells’ transcription factors such as OCT3/4, SOX2, KLF4, and C-Myc. These reprogrammed cells are called induced pluripotent stem cells (iPS).

2- Adult Tissue-Specific Stem cells

Adult stem cells or adult tissue-specific stem cells are non-embryonic stem cells found in the tissues and organs of adult individuals. They have the specific characteristics of self-renewal and generate differentiated and specialized cells that contribute to tissue homeostasis and regeneration following injuries or diseases. They are found in several organs including the brain, liver, bone marrow, eyes, gut, skin, and muscle.

3- Mesenchymal Stem Cells (MSCs)

Mesenchymal stem cells are multipotent stromal stem cells that can only differentiate into bone, cartilage, muscle, tendons, ligaments, and neurons. They are found in the bone marrow.

4- Umbilical Stem Cells

These stem cells are recovered from post-natal (after birth) umbilical cords that contain HSCs and MSCs found in the umbilical cord blood cells, umbilical cord vein, and amnion and placenta. Clinically, they are used to treat blood diseases such as leukemia.

5- Bone Marrow Stem Cells

The bone marrow is the niche of hematopoietic stem cells (HSCs) that generate cells of the blood which contribute to the transport of nutrients and oxygen, coagulation, and immunity. HSCs produce two types of progenitor cells: myeloid progenitors and lymphoid progenitors.

The myeloid progenitors generate erythrocytes (red blood cells), platelets for coagulation, and myeloblasts that produce basophil, eosinophil, neutrophil, and monocytes that contribute to immunity. Lymphoid progenitors produce lymphocytes T, and lymphocytes B are also key players in immunity.

Like umbilical stem cells that contain hematopoietic stem cells (HSCs), bone marrow stem cells are also clinically used to treat blood diseases such as leukemia.

III. What Are the Applications of Regenerative Medicine?

Several clinical trials are taking place to assess the feasibility of using stem cells for the treatment of diseases and conditions. These can be assessed through clinicaltrials.gov.

1- Neurology Applications

Stem cells are being clinically tested for the treatment of Parkinson’s disease using embryonic dopamine neurons, while MSCs, bone marrow cells, and HSCs are being tested for the treatment of paraplegia, spinal cord injury, and multiple sclerosis.

2- Respiratory Applications

MSCs derived from the umbilical cord and bone marrow are being investigated for the treatment of chronic lung disease and idiopathic pulmonary fibrosis.

3- Cardiology Applications

For the treatment of heart failure and ischemic cardiomyopathy, MSCs are being tested through intracardiac injections.

4- Rheumatology Applications

MSCs and HSCs are being investigated for the treatment of osteoarthritis and osteogenesis imperfecta by direct injection into the articulations or through perfusion.

5- Hematology Applications

Through perfusion alone or in combination with hematopoietic stem cell transplantation, MSCs are being tested for the treatment of Graft versus Host Disease (GvHD).

6- Gastroenterology Applications

Treatments of Liver disease and decompensated liver disease are being tested using intravenous injection or diffusion of MSCs, while HSCs are being investigated for the treatment of Crohn’s disease.

7- Orthopedics Applications

For the healing of fractures, osteoporosis, and joint resurfacing, bone grafts, MSCs and HSCs are being used.

8- Urology Applications

MSCs are being clinically tested for the prevention of kidney transplant rejection.

9- Endocrinology Applications

Stem cells from the cord blood are investigated for the treatment of insulin-resistant type II diabetes, while hematopoietic cell transplantation is used for diabetes type I.

10- Ophthalmology Applications

Endothelial stem cells from the retinal epithelium are used for the treatment of macular degeneration.

IV. Challenges of Regenerative Medicine.

Despite the significant advances in regenerative medicine, several challenging factors require further investigations to ensure its safe and ethical application for the treatment of diseases and conditions:

• The ethical use of embryonic stem cells is certainly an important factor in slowing down its application. Regenerative medicine is a subject of ethical, political, and religious controversies.
• Our body’s immune system that ensures our capacity to combat invading pathogens or cancer, may reject the stem cell therapy.
• The manufacturing of stem cell therapies is difficult to scale up and the associated cost is also significant.
• The stem cells that are used for stem cell therapies require screening to ensure that their genome is intact and does not contain mutations that could generate cancer upon transplantation into patients.

Conclusion

Regenerative medicine relies on the use of stem cells obtained from embryos, the umbilical cord, and adult stem cells that are found in some tissues of the adult body. However, regenerative medicine is also a multidisciplinary field that requires the contribution of other technologies such as stem cell and developmental biology, tissue engineering, nanotechnologies, chemical biology, and biomaterial engineering.

Although it is still considered an emerging therapeutic field, regenerative medicine is already showing an impact in the treatment of neurological, hematological, and rheumatological conditions. However, the progress of this field requires further clinical trials to ensure its safety and development in the clinic.

Solid data obtained through clinical trials with clear healthcare benefits will certainly promote public awareness about regenerative medicine which is already subject to ethical, political, and religious controversies.

References

[1] Atala, A., Lanza, R., Mikos, T. and Nerem, R. eds., 2018. Principles of regenerative medicine. Academic press.

[2] Regad, T., Sayers, T. and Rees, R., 2015. Principles of stem cell biology and cancer: future applications and therapeutics. John Wiley & Sons.

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