The biochemical and cellular pathway

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Maximally detailed descriiption of the biochemical and cellular pathway for the differentiation in cell culture of induced pluripotent stem cells into cardiomyocytes. Concerning bone-morphogenic protein-4, activin-a, CHIR99021, Wnt-C59, asorbic acid and B27 supplement.
Mention all types of receptors, ligands, signalling pathways i.e. SMADs, MAPK, JAK/STAT etc

 

 

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Induced pluripotent stem cells (iPSCs) can be differentiated into cardiomyocytes through a biochemical and cellular pathway which begins with the suppression of reprogramming factors to induce cell fate commitment. This is usually done by inducing bone-morphogenic protein-4 (BMP4), activin-A, CHIR99021, and Wnt-C59 in a cocktail of growth factors along with Asorbic Acid and B27 supplement (Kang et al., 2020).

The ligands bind to their respective receptors on the surface of the iPSCs resulting in activation of intracellular signalling pathways like SMADs, MAPK and Jak/STAT. The BMP4 binds to its receptor BMPR1a or BMPR2 on the cell surface leading to phosphorylation and dimerisation of SMAD proteins 1, 5 & 8 which then translocate inside the nucleus. Activin A binds to either ALK4 or ALK5 receptors triggering similar response as BMP but using different SMAD proteins 2 & 3 instead. Similarly, Wnt binding with FZD7 or FZD9 results in stabilizing βCatenin while CHIR99021 binding with FZD6 inhibits glycogen synthase kinase3β activity thus enhancing BetaCatenin concentration inside cytoplasm.

An accumulation of activated Beta Catenin leads to activation of TCF/LEF transcription factor that triggers expression of cardiac lineage specific genes such as MYOCARDIN related transcription factor A (MRTF-A) that supports myofibrillogenesis for cardiomyocyte differentiation (Wu et al., 2015). Further addition of ascorbic acid induces formation of cardiac precursors from mesodermal progenitors while B27 supplement helps in cardiomyocyte maturation by promoting electrical coupling among them (Tallquist et al., 2002).

In conclusion, regulated expression these various ligands results in efficient generation cardiomyoctyes from iPS cells via intermediates steps involving intracellular signalling pathways culminating in nuclear transactivation.

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