The Limitations Of Stem Cell Therapy

Limitations of Stem Cell Therapy Viraj

Abstract:

By definition, a stem cell is an undifferentiated cell of a multicellular organism which is capable of giving rise to indefinitely more cells of the same type, and from which certain other kinds of cell arise by differentiation. It is known that stem cells originate from various sources in humans including the embryo, umbilical cord, blood, and placenta. Stem cell therapy (SCT) uses these to regrow tissue damaged by injury or as a result of a degenerative, autoimmune, and genetic disorders.

Introduction:

Researchers in the field are continually engaged in new work including the generation of stem cell-derived biomaterials for use in the field of pharmacy genomics. ^{(Volarevic et al., 2018)}. Major strides are continuously being made in the area of SCT, so it is becoming increasingly important to thoroughly consider the scientific, ethical, and logistical limitations of stem cell therapy as modern science make it more accessible.

hESCs:

Human embryonic stem cells (hESCs) are the most useful in stem cell therapy as they are pluripotent. They have the ability to differentiate into cell types of all three germ layers (ectoderm, mesoderm, and endotherm) in vivo as well as in vitro conditions. ^{(Volarevic et al., 2018).} However, the pluripotency of hESCs is one of the properties that brings limitations in their use in stem cell therapy. ^{(Gorecka et al., 2019)}. Studies have shown that teratoma appears in between 33-100% of hESC-transplanted immunodeficient mice.^{(Volarevic et al., 2018)}. Therefore, increased incidence of teratomas following hESC therapy is a major limitation of SCT, as it occurs after the use of the preferred cell type for the majority of stem cell therapy.

Another limitation of stem cell therapy is the ethical dilemma surrounding the destruction of an embryo to collect hESCs. In order to collect hESCs, the 5-day-old human preimplantation embryo must be destroyed first. (King and Perrin, 2014). There is an underlying question that must be answered about stem cell therapy: Is it morally acceptable to introduce new therapies to cure disease at the expense of destroying a human embryo? (Volarevic et al., 2018). Those opposed to hESC research argue that the embryo possesses the ability to develop into a human being, and therefore the destruction of the embryo is unethical.(King and Perrin, 2014). Another restriction of stem cell therapy is its legality. In the United Kingdom, performing nuclear transfer of hESCs for reproductive or therapeutic use is banned, but nuclear transfer of hESCs is allowed for research purposes. (Volarevic et al., 2018). Although ongoing research makes hESC therapy applications potentially more useful, it is not possible to put it into practice at this time.

iPSCs:

An alternative to the use of embryonic stem cells in SCT is the use of induced pluripotent stem cells.(Gorecka et al., 2019). These cells are similar to embryonic stem cells in karyotype (the number and visual appearance of the chromosomes in the cell nuclei of an organism or species) and importantly, they have a similar capacity for differentiation (so they are also prone to teratoma formation). (Volarevic et al., 2018). iPSCs are seen to be morally superior when compared to hESCs as their generation does not involve for the destruction of human embryos. Having said that, uncontrolled proliferation of transplanted undifferentiated iPSCs can result in the undesired differentiation of iPSCs into a large variety of somatic cells (any cell of the body except sperm and egg cells). As such, more efficient methods for the generation of pure populations of iPSC-derived cells need to be established. This remains an obstacle for the use of iPSCs stem cell therapy in regenerative medicine.(Volarevic et al., 2018). In order to prevent the unwanted differentiation of iPSCs and make them safe for use in stem cell therapy, non-integrative technology may have to be developed, with progress being made in the use of protein and small particle transfer.(Gorecka et al., 2019).

The use of stem cells in cardiac therapy is a promising prospect. There are a few hurdles that need to be overcome in order to make it safe. Ideally, a stem cell would differentiate into cardiomyocytes that interact mechanically and electrically with neighbouring myocytes. (M ller, Lemcke and David, 2018). It is accepted in the scientific community that stem cells release a number of agents, including chemokines, growth factors and cytokines. These have an effect on the environment around the cell. For example, stem cells reconstruct the myocardial vascular system by secreting (IGF-1) as a proangiogenic (a factor that promotes the formation of new blood vessels). However, IGF-1 also has the potency to inhibit the death of cardiomyocytes by apoptosis. This will prevent the death of damaged or fatigued cardiomyocytes which is detrimental to the cardiac health of any patients receiving stem cell cardiac therapy.(M ller, Lemcke and David, 2018)

Stem Cell Markers:

The safety of the use of stem cells in medical therapy must be considered carefully before treatments can be widely used. In particular, the inability to properly track stem cells after their transplantation is a troubling deficit. This is due to the non-specific nature of common stem cell markers coupled with their unreliability. An example of this is the use of a class of monoclonal antibody known as anti-CD73s. This monoclonal antibody is specific to an enzyme called CD73 which is expressed by a variety of cell types, including lymphocytes, endothelial cells, smooth muscle cells, epithelial cells, and fibroblasts. (Lin et al., 2013). From an earlier study (Barry et al., 2001), two examples of anti-CD73 monoclonal antibodies called SH3 and SH4 were found to have specificity for stem cells, however, in the 20 years since this was claimed, there has been to evidence that any anti-CD73 antibody can detect stem cells in vivo. This is a significant limitation when it comes to detecting cells after transplantation as CD73 is a cell surface marker that is widely used to track stem cells in the lab, as it is expressed by more than 95% of stem cells so is used widely. (Lin et al., 2013). In an in vivo situation, an alternative must be deemed effective before stem cell therapy can become commonly practiced.

A review article written by Kolf et al. concluded that a cell surface marker known as Stro-1 is the best-known stem cell marker. However, immunostaining of tissues with an antibody that is specific to Stro-1 produced a positive result in vascular endothelium.(Lin et al., 2011). Another study in which Stro-1 antibody was compared to an endothelial-specific antibody in immunofluorescence analysis of blood vessel-rich tissues and found extensive overlaps between the endothelial antibody and the Stro-1 marker stains and therefore confirmed the endothelial identity of Stro-1. Thus, although expressed in cultured stem cells, Stro-1 as an in vivo stem cell marker is compromised by its concurrent expression in the endothelium.(Lin et al., 2013) Again, this is a major limitation of stem cell therapy because even the most favoured stem cell marker has shown that it is not suitable for in vivo use in humans, and as such, alternatives must be found.

Conclusion:

To conclude, there are a number of limitations for the use of stem cells in the use of medical practice that must be considered before the treatment (which has great potential) is implemented. Firstly, ethical issues must be confronted if hESCs (the most versatile type of stem cells) are to be used in therapy. In addition, the tendency of hESCs to form teratoma tumours must be first acknowledged and then controlled by the scientific community, by either adapting hESCs or finding alternatives. The most encouraging alternative to embryonic stem cells, iPSCs, are still prone to undesired differentiation into a variety of somatic cell types and techniques to implement iPSCs need to be refined further. Further still, the way stem cells interact within the body is a limitation to their use in therapy, whether that be the inhibition of apoptosis of cardiac tissue or the inability to track the cells following introduction to the body. We must identify and address some of the limitations of stem cell therapy whilst eagerly anticipating the significant contributions it will surely make to the scientific community.

Bibliography:

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Gorecka, J. et al. (2019) The potential and limitations of induced pluripotent stem cells to achieve wound healing., Stem cell research therapy, 10(1), p. 87. doi: 10.1186/s13287-019-1185-1.

King, N. M. and Perrin, J. (2014) Ethical issues in stem cell research and therapy., Stem cell research therapy, 5(4), p. 85. doi: 10.1186/scrt474.

Lin, C.-S. et al. (2013) Commonly used mesenchymal stem cell markers and tracking labels: Limitations and challenges., Histology and histopathology, 28(9), pp. 1109 1116. doi: 10.14670/HH-28.1109.

Lin, G. et al. (2011) Tissue distribution of mesenchymal stem cell marker Stro-1., Stem cells and development, 20(10), pp. 1747 1752. doi: 10.1089/scd.2010.0564.

M ller, P., Lemcke, H. and David, R. (2018) Stem Cell Therapy in Heart Diseases - Cell Types, Mechanisms and Improvement Strategies., Cellular physiology and biochemistry: international journal of experimental cellular physiology, biochemistry, and pharmacology, 48(6), pp. 2607 2655. doi: 10.1159/000492704.

Volarevic, V. et al. (2018) Ethical and Safety Issues of Stem Cell-Based Therapy., International journal of medical sciences, 15(1), pp. 36 45. doi: 10.7150/ijms.21666.