Stem Cells


Stem Cells

Stem cells are the source of all specialized cells that form organs and tissues in the human body and, unlike mature cells, they are capable of long-term self-renewal and can replicate and divide themselves for long periods.1 They are broadly categorized as totipotent, pluripotent, multipotent, and unipotent, depending on their ability to generate different cell types.2 The determination of a stem cell’s lineage and its function is regulated by a combination of extrinsic – chemical factors and physical contact – or intrinsic influences, such as genetic programming.3 Stem cells divide to form daughter cells that either become new stem cells or differentiate into specialized cells under the right conditions in the human body or laboratory. Lab-grown human stem cells can offer improved models for testing new treatments, but there are many ethical and immunological challenges regarding their use that are not yet fully addressed.

Types of stem cells based on their differentiation potential

Totipotent stem cells (TSCs) have the highest differential potential, which allows them to form both embryonic – all three germ layers – and extraembryonic structures – placenta, yolk sac, and umbilical cord. The zygote and early cleavage-stage blastomeres are examples of known totipotent cells in the human body.4

Pluripotent stem cells (PSCs) can differentiate into all specialized cells of a whole organism but not into extraembryonic or placental cells, which distinguishes them from TSCs. PSCs can be sub-grouped into embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs).1

  • ESCs are the 50-100 PSCs found in a blastocyst that has not yet been implanted in the uterus. ESCs used in research are derived from unused embryos resulting from in vitro fertilization procedures. These cells can proliferate indefinitely and differentiate into mature tissue types, but most of the existing studies are based on mouse models, and further trials and regulatory standards are needed for human applications.
  • iPSCs are derived from mature somatic cells by reprogramming, activated by the expression of the octamer-binding transcription factor (Oct4), sex-determining region Y (Sox2), Kruppel-like factor 4 (Klf4), and the Myc gene. As pluripotent cells can propagate indefinitely into any kind of cell, they can be an unlimited source for replacing lost or diseased tissues. Another advantage of iPSCs is that they bypass the need for embryos in stem cell therapy, and reduce the risk of immune rejection as they are autologous. Researchers currently focusing on iPSCs hope that they may be used to help treat neurodegenerative diseases.5

Multipotent stem cells have a narrower spectrum of differentiation than PSCs, but specialize in discrete cells of specific lineages, for example, hematopoietic stem cells (HSCs) that generate all types of blood cells. These cells have the characteristic plasticity to become all the progenitor cells for a particular germ layer, and are a viable option for clinical use.1

Oligopotent stem cells are further restricted in their capacity to differentiate and form two or more lineages within a specific tissue. Descending from multipotent HSCs, myeloid progenitor cells can be considered oligopotent as they can give rise to several types of white blood cells but cannot generate other cells, for example, red blood cells.

Unipotent stem cells can only differentiate into one type of specialized cell. For example, muscle stem cells can only mature into myocytes in a unidirectional manner. Because these unipotent cells can divide repeatedly, they are good candidates for therapeutic and regenerative medicine.5

Types of stem cells based on their origin and destined pathway

Stem cells can also be classified according to their source of origin, as follows:

  • ESCs are PSCs are derived from the embryo (see above).
  • Fetal stem cells are multipotent cells that are found in the organs of fetuses, and can differentiate into pluripotent and hematopoietic stem cells.
  • Infant stem cells are multipotent stem cells that exist in the umbilical cord.
  • Adult stem cells are found in the tissues of both children and adults. They give rise to committed progenitors that are an intermediate cell type, and further divide to generate fully differentiated and functional cells. Adult stem cells are multi- to unipotent, with each stem cell type only capable of generating a specific cell lineage. They are also more likely to inherit abnormalities through environmental factors or mutations, which might limit their potential as therapeutic agents. The following subtypes are recognized:
    • Mesenchymal stem cells (MSCs) are spindle-shaped cells that can be isolated from adult and perinatal tissues and give rise to bone, cartilage, and fat. These cells have a fibroblast-like appearance and can be readily isolated from the bone marrow and adipose tissue.6
    • Neural stem cells (NSCs) give rise to neurons and their supporting cells, including oligodendrocytes and astrocytes. NSCs have been a focal point for cell-based therapeutic strategies in diseases associated with the brain and spinal cord.7
    • HSCs proliferate and progress through a series of lineage commitment steps, determining whether the cells are myeloid or lymphoid.8 Structurally, HSCs resemble lymphocytes in shape; they are round, non-adherent cells with a spherical nucleus and a low cytoplasm-to-nucleus ratio.
    • Gastrointestinal stem cells reside in a niche in the intestinal crypts and gastric glands. They have characteristic properties of self-renewal and clonogenicity, and have the potential to generate into different cell types of the intestinal epithelium.9
    • Epidermal stem cells develop into cells such as keratinocytes, which make up the protective layer of skin. They are established in the basal layer of the skin and play a role in maintaining cellular regeneration of normal skin, wound healing, and neoplasm formation.10
    • Hepatic stem cells exist in the liver and, although they are yet to be characterized, they are known to differentiate into hepatocytes when stimulated by chronic liver injury.11
    • Pancreatic stem cells are multipotent, and studies so far suggest that they arise from the developing foregut endoderm during embryogenesis.12
    • Cancer stem cells (CSCs) are a small subpopulation of cells within tumors that are resistant to conventional chemotherapy and radiotherapy, and are considered the origin of metastasis and tumor recurrence. They differ from healthy stem cells in terms of their signaling pathways (Wnt/ β-catenin, Hh, Bmi. NF-ĸB, MAPK, and Notch for CSCs) and dependence on the tumor microenvironment (TME). They reside in niches – anatomically distinct regions within the TME – that maintain their principal properties, protect them from the immune system, and enhance their metastatic potential. They are now being identified as targets for new anti-cancer drugs, however, more evidence is required to understand the correlation between the proportion of treatment-resistant CSCs within a tumor and the aggressiveness of cancer.13

Emerging research

Stem cell transplants are standard treatments for cancers, such as leukemias and lymphomas, where they replenish the body’s supply of HSCs when the cancerous bone marrow has been destroyed by chemoradiation. The two main types are allogenic and autologous, depending on whether the donor stem cells are obtained from the patient’s own body or from another person. Moreover, the groundbreaking switch from using allogeneic to autologous iPSCs could eliminate problems such as immune rejection.14

Somatic cells from a patient can be used to generate diseased iPSCs, which can be repaired by gene therapy and then used to generate healthy somatic cells to transplant to the site of injury or tissue degeneration. They may also be used to produce unrepaired somatic cells for disease modeling or drug screening.15

HSCs offer a unique therapeutic opportunity to treat certain hematologic diseases. Reintroducing healthy HSCs can result in corrective changes at the starting point of hematopoiesis that can be directed through multiple cell lines. This approach is now evolving to investigate the use of a genetic modification of autologous HSCs.16,17

Hematopoietic stem and progenitor cell (HSPC) gene therapy has emerged as an effective modality for monogenic disorders of the blood. When reinfused, genetically modified HSPCs undergo self-renewal and establish a population of modified cells, which pass the transgene to daughter blood cells on differentiation.18

In therapeutic cloning, ESCs are generated by transferring the nucleus of a mature skin cell into a denucleated egg cell which forms the embryo. Genetically donor matched ESCs can then be obtained from this embryo to study genetic or inherited diseases. Another futuristic hope for therapeutic cloning is that genetically matched tissues could be regenerated to replace or repair organs with a very low risk of graft rejection.19

Tools to study stem cells

Tools such as RT-PCR, flow cytometry, and fluorescence microscopy are used to study a combination of cell markers that differentiate stem cells and direct their use in research. High throughput proteomic techniques can also be used to decipher the protein constituents of MSCs, as well as to quantify the changes that occur in physiological or pathological conditions.

Cell markers

Overview of the markers stem cells:20,21,22

Cell marker Stem cell type Location
CD73 MSCs, CSCs Surface
CD90 MSCs, HSCs Surface
CD92 BMSCs Surface
CD105 MSCs Surface
CD110- Stem cells Surface
CD123low HSCs Surface
CD131 HSCs Surface
CD133 HSCs Surface
CD143 MSCs Surface
CD172a Brain SCs Surface
CD174 Stem cell subsets Surface
CD318 HSCs Surface
CD326 ESCs Surface
CD340 HSCs Surface
CD349 MSCs Surface
CD362 MSCs Surface
CD369 HSPCs Surface
SSEA-3 ESCs/iPSCs Surface
SSEA-4 ESCs/iPSCs Surface
TRA-1-60 Pluripotency marker Surface
TRA-1-81 Pluripotency marker Surface
CD34 HSCs Surface
Stro-1 MSCs Surface
SSEA-1 negative ESCs and iPSCs Surface
CD49f HSCs Surface
CD44 MSCs Surface
CD271 MSCs Surface
CD15 CSCs Surface
CD24 CSCs Surface
CD34 CSCs Surface
CD44 CSCs Surface
CD45 CSCs Surface
CD49f CSCs Surface
CD166 CSCs Surface
CD338 CSCs Surface
Nanog ESCs/iPSCs Intracellular
Oct3/4 ESCs/iPSCs Intracellular
Sox2 ESCs/iPSCs Intracellular
Pax6 NSCs Intracellular
Sox1 NSCs Intracellular
Nestin NSCs Intracellular
Musahi-1 NSCs Intracellular

References

1. Biehl, J. K., & Russell, B. (2009). Introduction to stem cell therapy. The Journal of cardiovascular nursing. 24(2):98–105. https://doi.org/10.1097/JCN.0b013e318197a6a5

2. Vimal K., Abhishek Saini et al. (2016). Describing the Stem Cell Potency: The Various Methods of Functional Assessment and In silico Diagnostics. Front. Cell. Dev. Biol. https://doi.org/10.3389/fcell.2016.00134

3. Preston SL, Alison MR et al. (2003). The new stem cell biology: something for everyone. Molecular Pathology. 56:86-96. https://mp.bmj.com/content/56/2/86

4. Condic M. L. (2014). Totipotency: what it is and what it is not. Stem cells and development. 23(8), 796–812. https://doi.org/10.1089/scd.2013.0364

5. Zakrzewski, W., Dobrzyński, M. et al. (2019). Stem cells: past, present, and future. Stem Cell Res Ther. 10:68. https://doi.org/10.1186/s13287-019-1165-5

6. Andrzejewska, A., Lukomska, B., & Janowski, M. (2019). Concise Review: Mesenchymal Stem Cells: From Roots to Boost. Stem cells (Dayton, Ohio), 37(7), 855–864. https://doi.org/10.1002/stem.3016

7. Zhao, X., & Moore, D. L. (2018). Neural stem cells: developmental mechanisms and disease modeling. Cell and tissue research, 371(1), 1–6. https://doi.org/10.1007/s00441-017-2738-1

8. Kondo M. (2010). Lymphoid and myeloid lineage commitment in multipotent hematopoietic progenitors. Immunological reviews, 238(1), 37–46. https://doi.org/10.1111/j.1600-065X.2010.00963.x

9. Pirvulet V. (2015). Gastrointestinal stem cell up-to-date. Journal of medicine and life, 8(2), 245–249.

10. Ronghua Yang, Jingru Wang, Xiaodong Chen, Yan Shi, & Julin Xie, Epidermal Stem Cells in Wound Healing and Regeneration. Stem Cells International, vol. 2020, Article ID 9148310, page 11, 2020. https://doi.org/10.1155/2020/9148310

11. Bruno S, Herrera Sanchez MB, Chiabotto G, Fonsato V, Navarro-Tableros V, Pasquino C, Tapparo M and Camussi G (2021) Human Liver Stem Cells: A Liver-Derived Mesenchymal Stromal Cell-Like Population With Pro-regenerative Properties. Front. Cell Dev. Biol. 9:644088. doi: 10.3389/fcell.2021.644088

12. EL Barky AR, Ali EMM, Mohamed TM. (2017). Stem Cells, Classifications, and their Clinical Applications. Am J Pharmacol Ther. 1(1): 001-007.

13. MdShaifur Rahman, Hossen Mohammed Jamil et al. (2016). Stem cell and cancer stem cell: A tale of two cells. Progress in stem cell. 3:2, 97-108. https://doi.org/10.15419/psc.v3i02.124

14. Madrid, M., Sumen, C., Aivio, S., & Saklayen, N. (2021). Autologous induced pluripotent stem cell–based cell therapies: Promise, progress, and challenges. Current Protocols, 1, e88. doi: 10.1002/cpz1.88

15. Singh Vimal K., Kalsan Manisha et al. (2015). Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery. Frontiers in Cell and Development Biology. Vol. 3. DOI=10.3389/fcell.2015.00002

16. https://www.nice.org.uk/news/article/nice-approves-gene-therapy-for-rare-bubble-baby-syndrome

17. Sagoo, P, Gaspar, HB. (2021) The transformative potential of HSC gene therapy as a genetic medicine. Gene Ther. https://doi.org/10.1038/s41434-021-00261-x

18. Ferrari G, Thrasher AJ, Aiuti A. (2021). Gene therapy using haematopoietic stem and progenitor cells. Nat Rev Genet. 216-234. doi: 10.1038/s41576-020-00298-5. Epub 2020 Dec 10. PMID: 33303992.

19. Kfoury C. (2007). Therapeutic cloning: promises and issues. McGill journal of medicine: MJM: an international forum for the advancement of medical sciences by students.10(2), 112–120

20. Walcher Lia, Kistenmacher Ann-Kathrin et al. (2020). Cancer Stem Cells—Origins and Biomarkers: Perspectives for Targeted Personalized Therapies. Frontiers in Immunology. Vol. 11. DOI=10.3389/fimmu.2020.01280

21. Calloni, R., Cordero, E. A. et al. (2013). Reviewing and updating the major molecular markers for stem cells. Stem cells and development. 22(9):1455–1476. https://doi.org/10.1089/scd.2012.0637

22. Zhao, W., Ji, X. et al. (2012). Embryonic stem cell markers. Molecules (Basel, Switzerland), 17(6), 6196–6236. https://doi.org/10.3390/molecules17066196

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