Promises of iPS Cells in Regenerative Medicine

1. Abstract

This study aims to look at the advantages of embryonic stem cell research over adult stem cell research on the basis of the markers of differentiation potential, manipulation, and replication. Then, the paper will look at the scope of induced pluripotent stem cells, that aren’t subject to the ethical constraints of the extraction of embryonic stem cells, however, possess their properties of indefinite self-renewal and versatility. 

2. Keywords

Embryonic stem cells, adult stem cells, induced pluripotent stem cells 

3. Introduction

A stem cell is a reserve cell that each creature has in its body. It possesses the ability to grow into any cell that is required by the body and to multiply so that it can replace any dead or damaged adult cells. Stem cells, both embryonic and adult, possess the ability to differentiate into new cell types. They can divide and self-renew indefinitely. Embryonic stem cells are pluripotent and they can undergo spontaneous differentiation into three germ layers. They come from embryos that are three to five years old, which is referred to as blastocyst. Blastocyst is an early stage of the embryo that reaches approximately 4-5 days after fertilisation. It would consist of 50-150 cells in number. These embryos are generated through the in vitro fertilisation process. On the other hand, adult stem cells, which are either unipotent or multipotent, possess limited ability to undergo differentiation and repair the tissues. In addition, adult stem cells can only grow in certain parts of the body which include breasts, intestine, bone marrow, fat tissue, brain, testes, etc. The adult stem cells are derived from adult tissue, and depending on the tissues they are derived from, they have the ability to regenerate into all the cell types of the organ from which they originate.

Stem cell therapies are used to treat patients of leukaemia, Hodgkin disease, non-Hodgkin lymphoma, certain solid tumour cancers, aplastic anaemia, immunodeficiencies and inherited conditions of metabolism. They are used in the treatments of type 1 diabetes, Parkinson’s disease, amyotrophic lateral sclerosis, heart failure, osteoarthritis and other conditions.

Despite all these advantages, both embryonic stem cell research and adult stem cell research are confronted with limitations. Embryonic stem cell research invites a lot of ethical and policy problems as it involves the destruction of embryos. On the other hand, the major drawback associated with adult stem cells is that they possess limited capacity of differentiation and they cannot be utilised to produce all cell types.

That’s where the research of induced pluripotent stem cells (iPS cells) gains prominence. Somatic cells can be reprogrammed to form induced pluripotent stem cells (iPS cells) which possess the properties of embryonic stem cells.

4. Literature review

Stem cell research has led to the origin and development of regenerative medicine. However, in order to attain the full promises of regenerative medicine, it is essential to understand the full biology and characteristics of stem cells, implement their successful differentiation into functional tissues that can replace the defective ones, resolve the problems related to immune responses after replacement, and assess any oncogenic issues that limit their efficacy.

See Stem Cells : Promises Versus Limitations, https://www.liebertpub.com/doi/abs/10.1089/teb.2007.0216

Realising the full potential of stem cell research will not only benefit the development of cell replacement therapies, but will also provide a system for understanding the mechanisms of embryonic development and disease progression.

Stem cell research, especially embryonic stem cell research is constantly subjected to ethical and policy constraints. In any hSC research, sensitive downstream research, consent to donate materials for hSC research, early clinical trials of hSC therapies, oversight of hSC research and similar factors cause several dilemmas. These ethical and policy issues along with scientific challenges have to be resolved to realise the benefits of stem cell research effectively.

See Ethical issues in stem cell research, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726839/

Disputes regarding the onset of human personhood and human reproduction ethically challenge the derivation of pluripotent stem cell lines from oocytes and embryos. In the United States, the question of when human life begins has been highly controversial and closely linked to debates over abortion. Embryos have the potential to become human beings; if implanted into a woman’s uterus at the appropriate hormonal phase, an embryo could implant, develop into a foetus, and become a live-born child. Some people believe that “human life begins at conception”. According to their view, an embryo is a person with the same moral rights as an adult or a live-born child. Destruction of an embryo is a matter of concern with respect to their perspective. Taking a blastocyst and removing the inner cell mass to derive an embryonic stem cell line is considered as an infringement to the person’s rights.

Ethical concerns regarding oocyte donation for research also challenge the growth of the discipline.

• Medical risks of oocyte retrieval: The medical risks of oocyte retrieval include ovarian hyperstimulation syndrome, bleeding, infection, and complications of anaesthesia. These risks may be minimised by the exclusion of donors at high-risk for these complications, careful monitoring of the number of developing follicles, and adjusting the dose of human chorionic gonadotropin administered to induce ovulation or cancelling the cycle.
• Protecting the reproductive interests of women in infertility treatment: If infertile women share oocytes with researchers, either their own or those from a donor, their chances of becoming pregnant may be harmed because there will be fewer oocytes available for reproduction. In this situation, the physician carrying out oocyte retrieval and infertility care should give prime priority to the reproductive interests of women in infertility treatment. Reproductive uses should only employ the best quality oocytes.
• Payment to oocyte donors: Many jurisdictions have conflicting policies about payment to oocyte donors. Given that oocyte donors receive no financial benefit from their participation in research, there are no ethical issues with paying them back for out-of-pocket costs. Payment to oocyte donors beyond fair out-of-pocket costs, however, is debatable, and different jurisdictions may have internally inconsistent regulations.

• On the one hand, some object that such payments may induce women to undertake excessive risks, particularly poorly educated women who have limited options for employment.

However, others argue that it is discriminatory to forbid compensation to research oocyte donors while granting women thousands of dollars to endure identical procedures in order to donate oocytes for the treatment of infertility.

• Informed consent for oocyte donation: In California, CIRM has instituted heightened regulations for informed consent for oocyte donation for research. Whether or not donors value important information about oocyte donation—rather than just whether or not they have been informed of it—is the primary ethical concern.

•  In other research settings, research participants often fail to understand the information in detailed consent forms. CIRM thus reasons that disclosure is not sufficient to guarantee informed consent. In CIRM-funded research, oocyte donors must be asked questions to ensure that they comprehend the key information about oocyte donation. 

See Ethical issues in stem cell research, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726839/

Adult stem cells do not raise as many ethical concerns as embryonic stem cells as they don’t involve producing, using or destroying human embryos and they are not as controversial as embryonic stem cells. However, these cells cannot be expanded in vitro and have not been identified as pluripotent.  Their versatility and durability are limited as compared to adult stem cells. They may not be able to be manipulated to regenerate all cell types, which limits their promises to treating diseases. Adult stem cells are also more likely to contain irregularities due to environmental hazards, such as toxins, or from errors acquired by the cells during replication. However, recent research has identified that adult stem cells are more adaptable than was the first thought.

Genetic reprogramming allows researchers to make cells act similarly to embryonic stem cells. The unique nature of these cells lies in their capability, when cultured, for unlimited self–renewal and reproduction of all adult cell types in the course of their differentiation. They are derived from adult somatic cells that have been genetically reprogrammed to an embryonic stem cell-like state through the forced expression of genes and factors important for maintaining the defining properties of ES cells. Researchers have been able to take regular connective tissue cells and reprogram them to become functional heart cells. In studies, animals with heart failure that were injected with new heart cells had better heart function and survival time. Similarly, it enables the development of an unlimited source of any cell type for therapeutic purposes.

5. Methods

The primary research method for this study is a literature review and the analysis of the success of iPS cell technology in the development of a variety of functional cell types in vitro.  It includes the reprogramming of cardiac cells, iPS cells for Diabetes Mellitus, neural cells, etc.

 

The first stage of this study would involve the analysis of the regenerative potential of iPS cells for three cardiac cells: cardiomyocytes, endothelial cells and smooth muscle cells as per the studies of Mauritz and Zhang, Rufaihah and Nelson et al.

The second stage of this study would include the analysis of the derivation of insulin producing islet-like clusters from iPS cells according to the study of Tateishi et al.

The third stage of this study would involve the analysis of the differentiation of human ES cells into dopaminergic neurons with respect to the study of Swistowsk and the studies of Wernig and that of Tsuji et al.

Thereafter, the results of the studies would be taken into consideration and the success of the method in the generation of various functional cell types would be evaluated.

 

6.Results

Mauritz and Zhang individually proved the ability of iPS cells to differentiate into functional cardiomyocytes. Rufaihah et al., found that endothelial cells derived from iPS cells showed increased capillary density in a mouse model of peripheral arterial disease. Nelson et al., were able to use iPS cells to treat acute myocardial function. 

Tateishi et al., demonstrated that insulin-producing islet-like clusters (ILCs) can be derived from the human iPS cells.

Swistowsk et al., used a xenofree system to differentiate iPS cells into dopaminergic neurons.

Wernig et al., demonstrated that iPS cells can generate neuronal and glial cell types in culture.

Tsuji et al., used pre-evaluated iPS cells for the treatment of spinal cord injury.

See Induced pluripotent stem cells and their potential for basic and clinical sciences, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584308/

7. Discussion

There is indisputable evidence that iPS cells can be used to regenerate various functional cell types of cardiac cells, ILCs and neural cells with characteristics of ES cells in vitro. 

Nelson et al., demonstrated for the first time the efficacy of iPS cells to treat acute myocardial infarction. They showed that iPS cells derived from Mouse Embryonic Fibroblasts (MEF Feeder Cells) could restore post-ischemic contractile performance, ventricular wall thickness, and electrical stability while achieving in situ regeneration of cardiac, smooth muscle, and endothelial tissue. 

Regeneration of functional β cells from human stem cells offer great promise to the treatment of type 1 diabetes mellitus (T1DM). This may also benefit the patients with type 2 diabetes mellitus (T2DM) who need exogenous insulin. Tateishi et al., demonstrated that insulin-producing islet-like clusters (ILCs) can be generated from the human iPS cells under feeder-free conditions. The iPS cell derived ILCs not only contain C-peptide positive and glucagon-positive cells but also release C-peptide upon glucose stimulation. 

Swistowsk et al., demonstrated that using a xenofree system, iPS cells can be differentiated into committed neural stem cells and then to dopaminergic neurons. They were functional and they survived and improved behavioural deficits in 6-hydroxydopamine-lesioned rats after transplantation.

Wernig et al., showed that iPS cells can produce neuronal and glial cell types in culture. Upon transplantation into the foetal mouse brain, the cells differentiate into glia and neurons, including glutamatergic, GABAergic, and catecholaminergic subtypes. Furthermore, iPS cells were induced to differentiate into dopamine neurons of midbrain character and were able to improve behaviour in a rat model of Parkinson’s disease (PD) upon transplantation into the adult brain. 

Tsuji et al., used pre-evaluated iPS cells derived for treatment of spinal cord injury. These cells differentiated into all three neural lineages, participated in remyelination and induced the axonal regrowth of host 5HT+ serotonergic fibres, promoting locomotor function recovery without forming teratomas or other tumours.

See Induced pluripotent stem cells and their potential for basic and clinical sciences, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584308/

8. Conclusion

Embryonic stem cells, although being versatile and pluripotent, are subject to a plethora of ethical and policy constraints. However, their potential in cell-therapies cannot solely be ignored on the basis of moral grounds. Therefore, the technology of using induced pluripotent stem cells in regenerative medicine and cell-therapies is a great asset to the treatment of a variety of diseases. The fact that they don’t involve the destruction of embryos and aren’t subject to ethical challenges adds to the possibility of the technology.

9. References

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6. Medvedev, S.P., Shevchenko, A.I. and Zakian, S.M. (2010) Induced pluripotent stem cells: Problems and advantages when applying them in regenerative medicine, Acta Naturae. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347549/ (Accessed: 30 April 2024). 
7. Ye, L., Swingen, C. and Zhang, J. (2013) Induced pluripotent stem cells and their potential for basic and Clinical Sciences, Current cardiology reviews. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584308/ (Accessed: 30 April 2024).