Understanding the process by which dead cardiac muscle cells are replaced by scar is centrally important to regenerative medicine and its efforts to treat causes of heart damage such as myocardial ischemia. As contractile, organized cardiomyocytes die, scar-forming fibroblasts migrate into heart tissues, leading to reduced cardiac output and elasticity.

Mostert et al. demonstrated a more complex role for fibroblasts around cardiac damage, showing that they are involved in organizing cardiac muscle cells into a parallel orientation for heartbeat contraction. By coating flat substrate surfaces with different protein patterns, the group was able to control the distribution of cardiomyocytes and fibroblasts on substrates that were then subjected to cyclical stress, akin to effects of the beating heart following a heart attack.

The findings shed new light on how the mechanics of the beating heart play a role into its microscopic structure.

“The cardiac muscle cells are insensitive to this mechanical cue, except for when they are co-cultured in combination with fibroblasts in numbers that match the composition of the healthy and the diseased human heart,” Bouten said. “This implies that the cardiac fibroblasts, which are mostly seen as the foe in cardiac regeneration, can also be seen a friend, as they can chaperone the contractile muscle cells towards a functionally organized tissue.”

The researchers found that this chaperone relationship between cardiomyocytes and fibroblasts was not due to molecular signaling between the two cell types but rather occurred through mechanical relationships.

They plan to follow up on this result by exploiting this interaction to restore tissue organization in damaged cardiac tissue using living 3D engineered models.

Source: “Human pluripotent stem cell-derived cardiomyocytes align under cyclic strain when guided by cardiac fibroblasts,” by Dylan Mostert, Bart Groenen, Leda Klouda, Robert Passier, Marie-José Goumans, Nicholas A. Kurniawan, and Carlijn V. C. Bouten, APL Bioengineering (2022). The article can be accessed at https://doi.org/10.1063/5.0108914.