What Is Immunosenescence?

Immunosenescence is the process of aging of our immune system which starts to perform less compared to that of a young and healthy individual. Our immune system is divided into two types: innate immunity and acquired immunity also known as adaptive immunity.

1- Immunosenescence of the Innate Immunity

Innate immunity is the first line of defense against bacteria, viruses, fungi, and toxins. This immunity is not specific to the invading pathogen but is rather based on the recognition of conserved features of pathogens, which make it react faster to help destroy invaders [2].

Innate immunity is carried out by natural killer (NK) cells, neutrophils, macrophages, and dendritic cells that are produced in the bone marrow by the hematopoietic stem cells.

While neutrophils, macrophages, and dendritic cells perform their activities through phagocytosis (internalization and destruction of pathogens), Natural killer (NK) cells have a cytotoxic activity through the recognition and release of substances that cause the cell death of the pathogen.

Although the activity of natural killer (NK) cells remains preserved, the phagocytic activities against pathogens of neutrophils, macrophages, and dendritic cells are reduced. However, the number of these cells does not appear to be affected.

2- Immunosenescence of the Adaptive Immunity

Unlike innate immunity, adaptive immunity is a more specialized type of immunity that involves the white blood cells, lymphocytes B, and lymphocytes T [3].

Lymphocytes B are the cells that produce antibodies against pathogens and cancerous cells, while lymphocytes T recognize and destroy pathogens and cancer cells through their cytotoxic activity by inducing cell death.

Lymphocytes B and lymphocytes T are also produced in the bone marrow by the hematopoietic stem cells and become mature in the thymus and spleen and after their activation. With the increase in age, the quantity and quality of lymphocytes B and T immune responses are significantly changed resulting in an impaired immune response.

Older individuals have a diminished capacity to respond to novel antigens (molecules on the outside of pathogens or cancer cells) and vaccines which results in increased susceptibility to infection and the development of age-related diseases such as cancer.

3- Immunosenescence and Inflammation

The function of immune cells is regulated by intercellular (between cells) communications that are mediated by cytokines, a small group of proteins that regulate inflammation. Cytokines are released by different cells in the body, including cells of innate and adaptive immunity.

Some of the cytokines promote inflammation and are known as proinflammatory cytokines, while others have anti-inflammatory activity. During immunosenescence, there is an increase in proinflammatory cytokines due to alterations in the function of immune cells [4][5].

Can We Slowdown Immunosenescence?

Immunosenescence can be slowed down through diet and therapeutic drugs that reduce inflammation.

1- Diet

A diet that is rich in fruits, vegetables, whole grains, legumes, and olive oil (e.g., Mediterranean diet) and that contains fewer sugars and red meat (e.g., cured meat) has been shown to reduce inflammation [6].

Probiotics and prebiotics that have been shown to reduce inflammation can also be provided through diet. For instance, probiotics are found in yogurt, lactobacillus milk, some cheeses such as Gouda, cheddar, cottage cheese, mozzarella, pickles, sauerkraut, kefir, kimchi, tempeh, kombucha, and miso.

Prebiotics are found in carrots, quinoa, radishes, onions, chicory roots, konjac roots, oats, yams, garlic, barley, wheat bran, berries, apples, asparagus, bananas, leeks, chia seeds, flax seeds, cocoa, coconut, jicama root, and dandelion greens.

2- Micronutrients

Micronutrients, such as vitamins and minerals, are critical for the good performance of the immune system. For instance, people with zinc deficiency (e.g., in older individuals) experience increased susceptibility to a variety of pathogens.

Zinc has been shown to have to be crucial for the function of immune cells such as neutrophils, natural killer cells, T lymphocytes, and B lymphocytes [7].

Other micronutrients such as vitamin C also reduce inflammation through its anti-oxidative stress activity.

3- Probiotics and Prebiotics

Probiotics have been shown to prevent inflammation associated with allergies, diabetes type 2 (Diabetes Miletus), autoimmune diseases, rheumatoid arthritis, cancer.

Because they produce lactic acid, the probiotics, Lactobacillus and Bifidobacterium, suppress pathogens’ induction of immunomodulatory molecules that can induce inflammation.

Prebiotics induce the expression of cytokines that promote communication between immune cells leading to improved immune response and protection against infections and other diseases such as cancer and neurodegenerative diseases.

The administration of the prebiotic fructo-oligosaccharides improves antibody response to viral vaccines, upregulates toll-like receptor 2-mediated immune response, and increased phagocytosis, and the levels of NK cells and the anti-inflammatory IL-10.

4- Bioactive Compounds

Resveratrol is a polyphenol found in red wine that has antiaging and anti-diabetic properties and is used as a nutritional supplement. Resveratrol has been shown to increase the levels of the NAD-dependent deacetylase sirtuin-1 (SIRT-1), a protein that is involved in the cellular response to inflammatory, metabolic, and oxidative stressors.

Sulforaphane (SFN) is an isothiocyanate that is present in cruciferous vegetables such as cauliflower, cabbage, kale, garden cress, bok choy, broccoli, and Brussels sprouts. Sulforaphane has been shown to inhibit inflammation by inhibiting the pro-inflammatory factor NFkB and by promoting antioxidation via the induction of NrF2, a master regulator of detoxification, anti-inflammation, and antioxidation processes within the cells.

Conclusion

Immunosenescence is a natural process of aging that results in alterations in the immune system leading to increased susceptibility to infections, reduced response to vaccines, and increased inflammation. However, immunosenescence can be slowed down through appropriate and healthy diets and food supplements that help the function of the immune system.

References

[1] https://www.who.int/news-room/fact-sheets/detail/ageing-and-health

[2] Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K. and Walter, P., 2002. Innate immunity. In Molecular Biology of the Cell. 4th edition. Garland Science.

[3] Bonilla, F.A. and Oettgen, H.C., 2010. Adaptive immunity. Journal of Allergy and Clinical Immunology, 125(2), pp.S33-S40.

[4] Licastro, F., Candore, G., Lio, D., Porcellini, E., Colonna-Romano, G., Franceschi, C. and Caruso, C., 2005. Innate immunity and inflammation in ageing: a key for understanding age-related diseases. Immunity & Ageing, 2(1), pp.1-14.

[5] Miquel, J., 2009. An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamm-aging. Current pharmaceutical design, 15(26), pp.3003-3026.

[6] Vasto, S., Buscemi, S., Barera, A., Di Carlo, M., Accardi, G. and Caruso, C., 2014. Mediterranean diet and healthy ageing: a Sicilian perspective. Gerontology, 60(6), pp.508-518.

[7] Shankar, A.H. and Prasad, A.S., 1998. Zinc and immune function: the biological basis of altered resistance to infection. The American journal of clinical nutrition, 68(2), pp.447S-463S.

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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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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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