The application of iPSCs for generating tissues and organ grafts can solve many problems in organ transplants and improve the quality of life for millions of patients. iPSCs can be directed to generate specific cell types and can be used to replace ailing or degenerating tissues. The greatest advantage of this technique is that it overcomes graft-to-host incompatibility. It is for this reason that graft rejection by the hosts immune system decrease significantly. There are about 90,000 patients in the US transplant-waiting list, who need medical assistance, which can be addressed by stem cell technologies.
iPSCs technology can be used to transform terminally differentiated skin cells into kidney organoids which are functionally and structurally similar to those of kidney tissue in vivo. During kidneys healing process, a progenitor stem cell needs to become 20 types of cells, required for waste excretion, pH regulation, and restoration of water and electrolytic ions. The ex vivo kidney organoids are similar to fetal first-trimester kidneys for their structure and physiology. They can also be served as model for nephrotoxicity screening of drugs, disease modelling, and organ transplantation. However, there are many hurdles coming to the point of generation of fully functional kidney that can be dreamed for the near future.
iPSC-Liver buds have been developed from a mixture of three different kinds of stem cells, i.e., hepatocytes (for liver function) coaxed from iPSCs; endothelial stem cells (to form lining of blood vessels) from umbilical cord blood; and mesenchymal stem cells (to form connective tissue). This approach is like mimicking the fetal development and formation of a complex organ. In one experiment, after growing in vitro for a few days, the liver buds were transplanted into mice where the ‘liver’ quickly connected with the host blood vessels and continued to grow. It also performed regular liver functions including metabolizing drugs and producing liver-specific proteins. Further studies will monitor the longevity of the transplanted organ in the host body (ability to integrate or avoid rejection) and whether it will transform into tumors. Using this method, cells from one mouse could be used to test 1,000 drug compounds to treat liver disease, and reduce animal use by up to 50,000.
Loss of neurons in age-related macular degeneration (ARMD) is the common cause of blindness. At preclinical level, transplantation of iPSCs derived neuronal progenitor cells (NPCs) in rat limits progression of disease through generation of 5-6 layers of photoreceptor nuclei, restoring visual acuity.
Y. Tsai, B. Lu, B. Bakondi et al., “Human iPSC-derived neural progenitors preserve vision in an AMD-like model,” STEM CELLS, vol. 33, no. 8, pp. 2537–2549, 2015.
The high order brain functions, like emotions, anxiety, sleep, depression, appetite, breathing heartbeats, and so forth, are regulated by serotonin neurons. Generation of serotonin neurons occurs prior to birth, which are post mitotic in their nature. Any sort of developmental defect and degeneration of serotonin neurons might lead to neuronal disorders like bipolar disorder, depression, and schizophrenia-like psychiatric conditions. Manipulation of signaling in human iPSCs in defined culture conditions leads to an in vitro differentiation of iPSCs to serotonin-like neurons. These iPSCs-neurons primarily localize to rhombomere 2-3 segment of rostral raphe nucleus, exhibit electrophysiological properties similar to serotonin neurons, express hydroxylase 2, the developmental marker, and release serotonin in dose and time dependent manner. Transplantation of these neurons might cure from schizophrenia, bipolar disorder, and other neuropathological conditions.
J. Lu, X. Zhong, H. Liu et al., “Generation of serotonin neurons from human pluripotent stem cells,” Nature Biotechnology, vol. 34, no. 1, pp. 89–94, 2016.
Placenta, the cordial connection between mother and developing fetus, gets degenerated in certain pathophysiological conditions. Nuclear programming of OCT4 knock-out (KO) and wild type (WT) mice fibroblast through transient expression of GATA3, EOMES, TFAP2C, and +/− cMYC generates transgene independent trophoblast stem-like cells (iTSCs), which are highly similar to blastocyst derived TSCs for DNA methylation, H3K7ac, nucleosome deposition of H2A.X, and other epigenetic markings. Chimeric differentiation of iTSCs specifically gives rise to hemorrhagic lineages and placental tissue, bypassing pluripotency phase, opening an avenue for generation of fully functional placenta for human.
H. Benchetrit, S. Herman, N. Van Wietmarschen et al., “Extensive nuclear reprogramming underlies lineage conversion into functional trophoblast stem-like cells,” Cell Stem Cell, vol. 17, no. 5, pp. 543–556, 2015.
Degeneration of other organs and tissues also has been reported, like degeneration of lungs which might occur due to tuberculosis infection, fibrosis, and cancer. The underlying etiology for lung degeneration can be explained through organoid culture. Coaxing of iPSC into inert biomaterial and defined culture leads to formation of lung organoids that consisted of epithelial and mesenchymal cells, which can survive in culture for months. These organoids are miniature lung, resemble tissues of large airways and alveoli, and can be used for lung developmental studies and screening of antituberculotic and anticancer drugs.
B. R. Dye, D. R. Hill, M. A. Ferguson et al., “In vitro generation of human pluripotent stem cell derived lung organoids,” eLife, vol. 4, Article ID e05098, pp. 1–25, 2015.
Chronic wounds are rarely seen in otherwise healthy individuals; they are often associated with diabetes, obesity or old age. It has been estimated that 1-2% of people in developed countries suffer from chronic wounds in their lifetime [i].Current methods of wound management are palliative, but their ineffectiveness for complex wounds is an ongoing clinical problem. Healthcare systems are in desperate need of alternative therapies. Stem cells/ iPSCs are known to tremendously influence normal cell and tissue repair/regeneration, which is why a large proportion of research focuses on stem cells as the answer to treating chronic wounds. Self-renewing characteristics and multipotent differentiation potential of stem cells make them ideal candidates for the treatment of chronic wounds. Stem cell-based therapies bring about their effectiveness via a number of mechanisms. Stem cells can differentiate into new cells, secrete trophic factors, promote angiogenesis, modulate the immune system, improve wound closure, and also help in the development of new extracellular matrix (ECM).
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