Cooperation of Biological and Mechanical Signals in Cardiac Progenitor Cell Differentiation

Abstract

Three‐dimensional cardiac tissue‐specific scaffolds made of poly‐lactic acid (PLA) have an ordered array of square pores reproducing anisotropic cardiac‐like stiffness. The mechano‐physical features of the scaffolds favor cardiomyocyte adhesion and survival and combined with biological signals released by neonatal cardiomyocytes can accelerate cardiac stem cell differentiation by emulating in vitro cardiac niche.

Hippo Pathway Effectors Control Cardiac Progenitor Cell Fate by Acting as Dynamic Sensors of Substrate Mechanics and Nanostructure

“…25,38 Indeed, we demonstrate the up-regulation of such factors on 10 kPa gels, which Together with our in vivo results showing that YAP and TAZ up-regulation is triggered at the infarction border zone in adult mammalian heart, these data highlight a prompt response of resident cells to ECM stiffening in the postinfarcted myocardium.…”

“…12,20,30,41,42 Moreover, a specific response of tissue resident cardiac progenitor cells to substrate mechanical properties has been highlighted. 25,43 Recently, cell sensitivity to substrate composition has been associated with the ability of the Hippo pathway downstream effectors YAP and TAZ to act as transcriptional coactivators directly binding to lineage-specific effectors, thus acting as onÀoff relays in mechano-transduction. 18 These factors are also responsible for proper cardiac development during fetal life by controlling cardiomyocyte proliferation 21 and to promote adult cardiomyocyte survival after a myocardial insult.…”

Human Cardiac Progenitor Cell Grafts as Unrestricted Source of Supernumerary Cardiac Cells in Healthy Murine Hearts

“…In fact, among others, current protocols for cardiac cell therapy do not allow preserving an optimal cell viability/ function and maximizing differentiation yields, since progenitor cells are cultured under conventional conditions that have been established decades ago for differentiated cells and neglect the stem cell peculiar environment (niches) in vivo. The subsequent enzyme manipulation damages cell membrane and destroys the self-produced extracellular matrix required for progenitor cell homing and differentiation [19,23]. Finally, cells deprived of their natural adhesion structures are delivered as single cell suspension while exposed to distressing conditions (such as syringe and intraneedle pressure, and host critical ischemic microenvironment), to which they, usually embedded in the less-stressed atrial or apical myocardium [24], are not structurally and functionally adapted.…”

“…In fact, progenitor cells were delivered by leaning fragments ($0.5 million cells per each) of Sca-1 pos hCPC sheets on the visceral leaflet of the pericardial sac. Inside this cavity, Sca-1 pos hCPCs were supplied with an optimal array of biochemical signals (growth factors and cytokines released by the myocardium) and mechanostructural cues (e.g., stiffness and tessellation of the visceral pericardium [19,38]) able to trigger their migration and differentiation into the host myocardium [2,21]. Intriguingly, the host organ was represented by healthy hearts, in which, on the basis of the current vision, supernumerary terminally differentiated cardiomyocytes should not be accepted.…”

“…Immediately after isolation, cells were preplated for 30 minutes to recover the non-adherent-enriched fraction of nCMs, which were then seeded on fibronectin (2 lg/ ml), laminin (0.2%), gelatin (0.02%, Sigma-Aldrich) precoated plates or precoated glass chamber slides (BD Biosciences), in case of coculture experiments [19]. After 24 hours, Vybrant-labeled hCPCs were seeded directly onto cardiomyocytes (1:5) in complete medium.…”