Making cardiomyocytes with your chemistry set: Small molecule-induced cardiogenesis in somatic cells

Abstract

Cell transplantation is an attractive potential therapy for heart diseases. For example, myocardial infarction (MI) is a leading cause of mortality in many countries. Numerous medical interventions have been developed to stabilize patients with MI and, although this has increased survival rates, there is currently no clinically approved method to reverse the loss of cardiac muscle cells (cardiomyocytes) that accompanies this disease. Cell transplantation has been proposed as a method to replace cardiomyocytes, but a safe and reliable source of cardiogenic cells is required. An ideal source would be the patients' own somatic tissue cells, which could be converted into cardiogenic cells and transplanted into the site of MI. However, these are difficult to produce in large quantities and standardized protocols to produce cardiac cells would be advantageous for the research community. To achieve these research goals, small molecules represent attractive tools to control cell behavior. In this editorial, we introduce the use of small molecules in stem cell research and summarize their application to the induction of cardiogenesis in noncardiac cells. Exciting new developments in this field are discussed, which we hope will encourage cardiac stem cell biologists to further consider employing small molecules in their culture protocols.

Inhibition of Rho‑associated protein kinase improves the survival of human induced pluripotent stem cell‑derived cardiomyocytes after dissociation

“…In the present study, a directed cardiac differentiation method using small molecules (CHIR99021 and IWP2) that modulate Wnt signaling were applied, which achieved an efficiency of ~96.79%. Small molecules are advantageous compared with growth factors in that they are more cost effective, easy to store, more stable and more amenable to quality control (22).…”

Human Induced Pluripotent Stem Cells as a Platform for Personalized and Precision Cardiovascular Medicine

“…Small molecules are advantageous compared with growth factors in that they are cheaper to produce, simpler to store, more stable, and more amenable to quality control (137). Finally, the labor intensive process of embryoid body formation has been replaced by hiPSC differentiation in monolayer (145) or suspension cultures (37) that generate over 90% pure CM populations, and are amenable to automation and scale-up of 1.5-2 billion cells per liter of culture.…”

Human pluripotent stem cell models of cardiac disease: from mechanisms to therapies

“…The same signalling cues are required in monolayer differentiation as in EB-based procedures ( Kadari et al, 2015 ; Lian et al, 2012 ; Paige et al, 2010 ; van den Berg et al, 2014 ) but, because in this format the cells are more uniformly exposed to the differentiation signals, higher percentages and yields of cardiomyocytes can be obtained ( Zhang et al, 2012 ). Furthermore, the growth factor supplements in monolayer differentiations can be completely replaced with small molecules that exhibit less lot-to-lot variation compared to cytokines ( Burridge et al, 2014 ; Gonzalez et al, 2011 ; Kim et al, 2015 ; Lian et al, 2015 ; Minami et al, 2012 ). These small-molecule protocols have also been adapted to hPSCs cultured in suspension ( Kempf et al, 2014 ; Kempf et al, 2015 ).…”