| Recent work shows that lineage-specific transcription factors are sufficient toreprogram fully differentiated cells into either induced pluripotent stem cells (iPSCs)or other types of cells. These findings have demonstrated that a transcription factorcocktail can direct dramatic cell fate changes in committed somatic cells. The iPSCsfirst generated by Yamanaka and colleagues initiated a revolutionary era in cell-basedtherapies. Given the formation of tumors and the difficulty in the generation ofsufficient and pure iPSC-derived functional somatic cells, lineage conversion hasbecome a competitive strategy for generating the desired types of cells. This strategywas first applied in the direct conversion of fibroblasts to skeletal muscle via theectopic expression of MyoD. Subsequent examples included the induction ofmacrophagelike cells via the coexpression of PU.1and C/EBP in fibroblasts, theconversion of fibroblasts into functional neurons by delivering the transcription factorsAscl1, Brn2, and Myt1l, and the direct conversion of fibroblasts into functionalcardiomyocytes using a combination of the developmental transcription factors Gata4,Mef2c, and Tbx5. The usage of small chemical molecules, which can replacetransgenes for induction to ensure the utility of the resulting iPSCs, has not beenreported in lineage conversion.Obesity is an epidemic that has become a major problem throughout the world inrecent years. Adipose tissue is an important metabolic organ that is crucial forwhole-body insulin sensitivity and energy homeostasis. Adipogenesis or adipocytehyperplasia occurs throughout life in response to caloric intake that exceeds nutritionalrequirements. Being overweight or obese is associated with major health risks, such ascardiovascular disease, diabetes, nonalcoholic fatty liver disease, and cancer.Additionally, cachexia, a complex metabolic syndrome, results from the severewasting of both fat and fat-free mass in certain disease states, such as cancer andimmunodeficiency diseases. The conversion of adipocytes is therefore of greatsignificance for studies on the mechanism of adipogenesis, the prevention of some fat-related diseases, and therapies for cachexia-accompanied diseases.Some signaling pathways have been studied that play a vital role in regulatingadipogenesis. Transforming growth factor-beta (TGF-β) regulates the differentiationprogram of a variety of cell types, including myoblasts, chondrocytes, osteoblasts, andadipocytes. TGF-β can inhibit the adipose differentiation of some preadipocyte celllines, retain undifferentiated preadipocyte states, reverse the adipocyte phenotype ofsome maturate adipocytes, and reduce the expression of differentiation markers ofadipocytes. In TGF-β1transgenic mice, both white and brown adipose tissue masseswere reduced, and adipocyte differentiation was inhibited. Apart from TGF-b,Rho-associated kinase (ROCK) is also involved in adipogenesis. During adipogenesis,the actin cytoskeleton regulates the cell morphology of fibroblastic cells to round andfat-laden cells. ROCK regulates the reorganization of the actin cytoskeleton andcytoskeletal tension, and the inhibition of ROCK enhances adipogenesis.In this study, we treated PEFs with the TGF-β signaling pathway inhibitorSB431542and the ROCK signaling pathway inhibitor Thiazovivin to induceadipocytes. The induced adipocytes showed large lipid drops and the expression of themultiple fat marker genes. Moreover, we excluded the possibility that the inducedadipocytes originated from meschenchemal stem cell (MSC) or progenitor cells andconfirmed that the conversion occurred directly from the porcine embryonicfibroblasts (PEFs), without initial reversion to the pluripotent state. Our findingprovides a new method for adipocyte differentiation that may result from adipogenesis.Importantly, our chemical molecule cocktail may serve as a new method with greatpotential for generating converted cell lines for regenerative therapies. |
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