Please use this identifier to cite or link to this item:
Optimize the Methods of Reprogramming Chemically Induced Mesenchymal Stem Cells from Human Somatic Cells
Small molecules,Reprogramming,Rejuvenation,Human mesenchymal stem/stromal cell,Regenerative medicine,Cell therapy,
|Publication Year :||2017|
The induction of stem cells from human somatic cells through cellular reprogramming has revolutionized the way we study cell-fate decision and is heralding a new era of patient-specific regenerative medicine. Within several types of stem cells, human mesenchymal stromal/stem cells (hMSCs) hold great promises for regenerative medicine and perspectives in cell therapies. In terms of their multipotency, immuno-modularity, and without oncogenicity, hMSCs meet with high-class safety standard and have been attempted or ongoing to treat dozens of diseases through hundreds of clinical trials. However, hMSCs remain rare in adult bodies and require invasive treatment to isolate them, which is the main obstacle for autologous hMSC-based therapies. We recently demonstrated the first method to convert human dermal fibroblasts directly into functional MSC-like cells (induced MSCs, iMSCs) by a footprint-free method that avoiding DNA insertional mutagenesis. The method is based on a cocktail of six chemicals and the conversion time is within 6 days. iMSCs fulfill all the criteria of traditional hMSCs as determined by the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy (ISCT), including cell adhesion, marker expression and multipotency (ability to differentiate into osteoblasts, adipocytes, and chondrocytes) in a degree comparable to primary human bone marrow MSCs (BMMSCs). The preliminary data proved its significance and contribution to stem cell biology and regenerative medicine, and the results were published in Scientific Reports recently. Herein, in this thesis, I firstly identified the role of single factor included in the 6C cocktail (SB202190, SP600125, Go6983, Y27632, PD0325901, and CHIR99021) and found G06983 is the essential factor for reprogramming. After testing 120 different combinations, I then boosted the conversion rate from 38% to 78% based on a concise cocktail including the essential factor. Of note, the optimized cocktails including 4C (Go6983, CHIR99021, valproic acid (VPA), and dorsomorphin), 7C (6C plus VPA), 8C cocktail (7C plus dorsomorphin) show a promising performance of improving the functions of hMSCs. Accordingly, I will treat the senescent or aging primary hMSCs with the cocktails to test if the cocktails could improve the differentiation function of aging hMSCs in the future. Overall, my findings reveal a plastic strategy to enrich functional iMSCs with high efficiency from different sources by small molecule optimization, implying the potentials for cell fate remodeling and rejuvenation research. Thus, we expand the repertoire of applying small molecules to generate iMSCs from accessible cell types and ameliorate senescent/aging hMSCs, which have major implications for broader contribution in stem cell research and cell therapy of regenerative medicine.
|Appears in Collections:||分子與細胞生物學研究所|
Files in This Item:
|3.97 MB||Adobe PDF|
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.