**4. iPSC-MSCs and conclusion**

*Update on Mesenchymal and Induced Pluripotent Stem Cells*

Human iPSCs resemble human ESCs in many aspects including morphology, proliferation, differentiation potential, and pluripotency markers, but the epigenetic characteristics of human iPSCs are rather distinct [1, 2, 5, 61]. Although the utilization of iPSCs can avoid the obstacles and ethical concerns that limit the use of human ESCs, clinical application of human iPSCs still has a number of disadvantages that include chromosomal instability and tumorigenic potential, thus raising questions about the safety of their clinical utilization, and low reprogramming efficiency in addition to other concerns about their reproducibility for laboratory applications in disease modelling and drug screening

In 2006, Takahashi and Yamanaka were the first scientists to generate mouse iPSCs from dermal fibroblasts through retroviral-mediated ectopic expression of the four genes: OCT4, SOX2, KLF4, and c-MYC [1, 3, 4, 63]. Since this discovery, iPSCs have been used in many research and clinical trials, including disease modelling; drug toxicity as well as drug discovery; and regenerative medicine [3–5]. Reprogramming of iPSCs should have the following crucial requirements: species such as human or mouse; cell type such as blood cell or fibroblast; factor, drug, chemical, or other protein molecules such as miRNA, DNA modifying agent, NANOG, or LIN28; vector such as retrovirus or lentivirus; and disease with specific

Human iPSCs have revolutionized the field of human disease modelling with an enormous potential to serve as paradigm shifting platforms for preclinical trials, personalized clinical diagnosis, and personalized drug therapy [65]. During the last 13 years, significant developments and remarkable progress have been achieved in enhancing reprogramming techniques and their efficacy, increasing safety of derived iPSCs, and developing different delivery methods [61, 62]. The ability to generate iPSCs from human somatic cells provides tremendous promises and opportunities in basic research and regenerative medicine and can provide a wide range of applications including cell-based therapies, drug screening, and disease

The capacity of human iPSCs to retain patient-specific genomic, transcriptomic, proteomic, metabolomic, and other visualized big data information makes it possible to extend their applications beyond disease modelling into the field of personalized medicine which encompasses the adoption of novel prevention and treatment strategies based on individual variability [65]. The emergence of modern iPSC technology, with the capacity of these stem cells to undergo unlimited self-renewal and differentiation into any type of cell, has a great potential to advance translational applications including stem cell therapies and the generation of large-scale collections of cell lines for research purposes [67]. Recently, genomic editing technologies have been applied to correct the mutations in disease-specific iPSCs to create gene-corrected iPSCs that can be utilized in autologous stem cell-based therapies [64]. Nowadays, patient-specific iPSCs can be obtained by reprogramming of adult somatic cells by ectopic expression of pluripotency-associated transcription factors including OCT4, SOX2, KLF4, and c-MYC [64]. The availability of precisely generated iPSC-derived functional cells to replace or repair damaged tissues or organs will likely affect therapies of hematopoietic disorders and facilitate treatment of neurological, cardiovascular, hepatic, and retinal diseases and possibly diabetes mellitus [67]. Additionally, patient-specific iPSCs can bypass certain limitations of ESCs such as ethical concerns and immunological rejection [64]. The first clinical trial on cell-based therapy using iPSCs derived from patients to treat blindness

**3. iPSCs**

[1, 3, 5, 61, 62].

genetic mutation [1, 4, 5, 64].

modelling [61, 66].

**6**

started in Japan in September 2014 [67].

MSCs derived from iPSCs (iPSC-MSCs) exhibit higher proliferation rate and less senescence than BM-MSCs, and thus the former cells are emerging as an attractive therapeutic option for obtaining a substantial population of stem cells in a sustained manner for applications in regenerative medicine [68, 69]. Several studies using human iPSC-MSCs and their exosomes in human and animal studies have shown that transplantation of these cells can produce protection of the liver against hepatic ischemia; reduction in the volume of brain infarction and preservation of neurological function after acute intracranial hemorrhage; prevention of osteonecrosis of femoral head by promotion of local angiogenesis and prevention of bone loss; facilitation of cutaneous wound healing by promotion of collagen synthesis and angiogenesis; and modulation of differentiation and function of DCs in order to support their clinical application in DC-mediated immune disorders [69–73]. Thus, MSCs and iPSCs may reshape the future of medical therapeutics and may eventually become curative for several chronic and intractable medical illnesses [2, 4, 5].
