**Acknowledgements**

*4.2.3. Transplantation*

112 Tissue Regeneration

mutations are major concerns.

**5. Future and challenges**

present in the genome [118, 119].

the risk of jeopardizing genome integrity [115, 116].

state and chromosomal aberrations of cancer cells.

Given that hiPSCs are pluripotent stem cells which can be propagated unlimitedly and protocols for their differentiation into different cells/organoids have been established, hiPSC-derived micro-tissues are a potentially innovative material source for transplantation. In addition, immune rejection will be minimized when essentially returning the hiPSC-derived tissue to the original patient. For mature cells that have no or limited regenerative ability, such as cardiomyocytes, neurons, and pancreatic cells, hiPSC-derived cell/organoids are especially valuable for tissue repair. There are a series of clinical studies evaluating hiPSC-cells/organoids for treatment of neural degeneration, diabetes, heart failure, and retinal cells [114]. Although research on the application of hiPSCs in therapy have shown encouraging progress, there are some concerns involving the safety of hiPSC-based cell transplantation. Tumor risk and acquired gene

The original protocol to generate hiPSCs involves four transcriptional factors, but this method is not suitable because of its effect on genome integrity via the introduction of additional plasmids with exogenous genes. To make hiPSCs and their derivatives applicable for clinical uses, many improvements have been made to optimize the method for iPSC generation. The integration-free and chemical reprogramming protocols have been developed to minimize

In general, the genetic nature of a disease, the molecular editing platform used, the delivery method, and the targeted cells and organs are all factors that influence the efficacy of treatment and determine the likelihood of clinical benefits [117]. The CRISPR/Cas9 molecular scissor system has been used to edit the genomes of a diverse array of mammalian cell types and organisms with high efficiency and precision. Determining and overcoming the actual frequency of off-target activities is challenging, yet critical to the application of the technology in gene therapy. CRISPR/Cas9 technology allows the study of complex genetic diseases, including human cancer, in which multiple mutations and chromosomal translocations are

The potential application of hiPSC technology in cancer studies has been proposed, based on the idea of reprogramming cancer cells via hiPSC technology to cancer stem cell (CSC) state. CSCs are well-known as the origin of tumor development, the seeds for distant metastasis, and are critical in therapeutic resistance. Reprogramming the malignant cells back to their original state before the oncogenic transformation occurs [120], may provide tools for exploring the mechanisms of tumor initiation and progression *in vitro*, for studying the heterogeneity and origin of CSCs, and for producing cancer type-specific drug discovery. However, these reprogramming methods remain a challenge because of the cancer-specific epigenetic This work was supported by the National Institutes of Health (2R01CA151610), the Fashion Footwear Charitable Foundation of New York, Inc., the Margie and Robert E. Petersen Foundation, and the Linda and Jim Lippman Research Fund.
