Human-induced pluripotent stem cells (iPSCs) technology has ushered in an exciting new era for the fields of stem cell biology and regenerative medicine, as well as the fields of disease modeling and drug discovery. Because of their differentiation abilities and secretion of a variety of cytokines and growth factors, iPSCs have been extensively studied as novel agents for the treatment of many diseases.
Cell therapy is the practice of using living cells, either from a donor (allogeneic) or from the patient (autologous), as a therapeutic modality. Although there is great promise in cell therapy and the related field of tissue engineering, manufacturing the required cells can be daunting. This new therapeutic modality is not only complex to manufacture but also more sensitive to ostensibly minor process changes or variations, which may result in ineffective therapy. The iPSCs have similar characteristics to embryonic stem cells (ESCs), so by definition, they can self-renew indefinitely and become any cell type in the body. The huge potential of iPSCs for therapeutic purposes stems is that iPSCs have more predictive, but also faster, and cheaper capacity for cell therapy.
iPSCs play roles in the generation of replacement cells for transplantation therapies, as well as drug discovery and preclinical toxicity testing. In the context of existing drug testing platforms, such as animal studies, human clinical trials, animal iPSCs, and ESCs, human iPSCs provide advantages that can enhance the current approaches to drug discovery.
Fig.1 A schematic for human iPSC-based cell therapy. (Shi, 2017)
Accounting for more than 3.9 million deaths a year, cardiovascular diseases (CVDs) remain one of the most common causes of death in the world. Despite significant advancements in pharmacological and interventional treatment options, heart diseases represent an increasingly common disorder that carries a poor long-term prognosis. Innovative stem cell (SC) therapies have the potential to fundamentally alter the conventional treatment of CVDs by stimulating the regeneration of injured myocardium. Nowadays, several cardiac differentiation protocols have been developed for mouse and human iPSCs. However, functional analyzes of iPSC-derived cardiomyocytes revealed that these cells are immature and more related to embryonic rather than adult cardiomyocytes. In animal models, it was demonstrated that transplanted cardiomyocyte-like cells generated from iPSCs can integrate into the host tissue as well as to improve cardiac function and alleviate adverse remodeling processes. When compared with ESCs, patient-specific iPSCs-derived cells were thought to provide significant advantages, such as the lack of ethical issues and immune response.
Several research groups reported that iPSCs are capable of generating mature dopaminergic neurons, motor neurons (MN), and GABAergic interneurons, however, it is known that transplantation of mature neurons is characterized by poor cellular engraftment versus transplantation of neural progenitors. Consequently, transplantation of neural progenitors has been a focus and seems to be a promising approach for the treatment of Spinal cord injury (SCI). Several groups reported that autologous iPSC derived neural precursor cells (iPSC-NPC) could be efficiently derived and used for transplantation into rodents with SCI. Transplanted NPC predominantly gave rise to myelin-producing oligodendrocytes, leading to remyelination and improvement of nerve conduction. Moreover, iPSC-NPC migrated long distances, integrated into the spinal cord, and differentiated into mature neurons and glia, resulting in synaptic reconstruction and locomotor recovery. In addition, neurotrophic factors produced by iPSC-NPC, modulate immunopathological events following SCI. Besides, researchers have found that iPSC-derived astrocytes injected into the injured rodent spinal cord increased the sensitivity to mechanical stimulus but did not affect locomotor functions.
Human hepatocyte-like cells (HLC) can be efficiently derived from iPSC, however, using standard differentiation methods they are currently more fetal in their phenotype than adult primary hepatocyte. iPSCs have the ethical advantage of not requiring embryonic material and have the potential clinical advantage that they can be developed from autologous starting cells, thereby obviating the requirement for immunosuppression. The 3D culture of iPSCs has recently been shown to increase their maturity closer to that of mature hepatocytes emphasizing the need for an appropriate developmental niche for the cells. An exciting development was the demonstration that when human iPSCs were cultured with endothelial and mesenchymal cells they self-formed in vitro into small liver organoids that could be transplanted and had a metabolic and synthetic function. If iPSCs were used for the derivation of HLCs for the treatment of genetic liver diseases, then the autologous source would mean some form of gene surgery that would be required before use. Such an approach has been adopted in a preclinical model of alpha-1-antitrypsin deficiency.
hiPSCs provide the opportunity to generate patient-specific cell lines from which matched, autologous tissue could be manufactured. In the case of diabetes, these patient-specific hiPSC lines could be differentiated into β-like cells for autologous transplantation. These cells are generated by reprogramming somatic cells via gene overexpression into a pluripotent state. hiPSCs have been derived from several different patient populations with diabetes, including T2D, cystic fibrosis-related diabetes, maturity-onset diabetes of the young, Wolfram syndrome, and T1D. β-like cells have been differentiated from ND hiPSCs without obvious differences observed compared with hESC-derived cells. More recently, β-like cells from T1D patient-derived hiPSCs have been generated and compared with hiPSCs from ND donors.
Fig.2 Directed differentiation of hiPSCs into β-like cells. (Millman, 2017)
iPSCs have become an important scientific tool and are spurring advancements in basic research, disease modeling, drug development, and regenerative medicine. Equally important, this discovery unlocked many new opportunities for using iPSCs in both allogeneic and autologous cell therapy applications. With excellent scientists specialized in stem cell therapy, Creative Biolabs is capable to provide high-quality iPSC culture, characterization, and differentiation services to global researchers. Please feel free to contact us for a discussion with our scientists.
References
For Research Use Only. Not For Clinical Use.
