Influencing the Fate of Cardiac and Neural Stem Cell Differentiation Using Small Molecule Inhibitors of ALK5

Abstract

In this study, 50 tri‐substituted imidazoles (TIs), which are analogs of the small molecules TA‐01 and SB203580, were synthesized and screened for cardiomyogenic activities. Several TIs displayed cardiomyogenic activities when applied during the differentiation from days 3–5. The TIs did not affect the Wnt/β‐catenin pathway during cardiomyogenesis and the likely mechanism of action is through the inhibition of ALK5 of the TGFβ pathway. Interestingly, these TIs promoted the neural differentiation of human pluripotent stem cells (hPSCs) with a similar potency to that of the dual SMAD inhibitors SB431542/LDN‐193189 when dosed from days 1 to 9. The neural induction activities of the TIs correlated with their ALK5 inhibitory activities. This study reports the discovery of small molecule inhibitors of ALK5, which can promote the differentiation of hPSCs into cardiomyocytes or neural cells depending on the time of dosing, showing potential for the production of clinical‐grade cardiac/neural cells for regenerative therapy. Stem Cells Translational Medicine 2018;7:709–720

Neuro-regenerative imidazole-functionalized GelMA hydrogel loaded with hAMSC and SDF-1α promote stem cell differentiation and repair focal brain injury

“…Small molecule inducers play an important role in stem cell differentiation. Many tri-substituted imidazole molecules have been reported to promote the neural differentiation of human pluripotent stem cells 9 days post treatment [ 21 ]. We also verified whether imidazole group and SDF-1α in GelMA-imid/SDF-1α hydrogel could promote hAMSC differentiation, and the results were shown in Fig.…”

“…Furthermore, it is also very important to promote the differentiation of stem cells. Imidazole molecules are proved to promote the differentiation of pluripotent stem cells into neural cells [ 21 ]. It is also found that hydrogel containing imidazole groups can repair spinal cord injury by promoting ECM remodeling [ 22 ].…”

TGF-β and SHH Regulate Pluripotent Stem Cell Differentiation into Brain Microvascular Endothelial Cells in Generating an In Vitro Blood–Brain Barrier Model

“…The transforming growth factor-beta (TGF-β) signaling pathway is particularly crucial for embryonic development as it regulates pathophysiological processes of various organs [21]. Inhibition of the TGF-β signaling pathway accelerates the differentiation of neural-or endothelial-lineage cells, although the exact role of TGF-β signaling might vary depending on cell type and environment [22][23][24]. Therefore, we hypothesized that the regulation of the TGF-β signaling pathway could play key roles in enhancing the efficiency of hPSC differentiation into BME-like cells and acquiring the BBB phenotype by inducing co-differentiation into neural cells and ECs.…”

Protein and mRNA Quantification in Small Samples of Human Induced Pluripotent Stem-cell-derived Cardiomyocytes in 96-well Microplates

“…Due to high-cost considerations and the need for high-throughput mechanism insights into drug screening applications with human cells, such a system for protein quantification is particularly valuable for studies with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Indeed, the Wes has been already applied in several cases recently, including signaling pathway inquiries with hiPSC-CMs (35), cardiac pharmacology and toxicology (36), hiPSC differentiation (37,38), gene therapy (39) and quantifying ion channel expression to assess maturity (34).…”