Abstract
Paracrine factors can induce cardiac regeneration and repair post myocardial infarction by stimulating proliferation of cardiac cells and inducing the anti-fibrotic, antiapoptotic, and immunomodulatory effects of angiogenesis. Here, we screened a human secretome library, consisting of 923 growth factors, cytokines, and proteins with unknown function, in a phenotypic screen with human cardiac progenitor cells. The primary readout in the screen was proliferation measured by nuclear count. From this screen, we identified FGF1, FGF4, FGF9, FGF16, FGF18, and seven additional proteins that induce proliferation of cardiac progenitor cells. FGF9 and FGF16 belong to the same FGF subfamily, share high sequence identity, and are described to have similar receptor preferences. Interestingly, FGF16 was shown to be specific for proliferation of cardiac progenitor cells, whereas FGF9 also proliferated human cardiac fibroblasts. Biosensor analysis of receptor preferences and quantification of receptor abundances suggested that FGF16 and FGF9 bind to different FGF receptors on the cardiac progenitor cells and cardiac fibroblasts. FGF16 also proliferated naïve cardiac progenitor cells isolated from mouse heart and human cardiomyocytes derived from induced pluripotent cells. Taken together, the data suggest that FGF16 could be a suitable paracrine factor to induce cardiac regeneration and repair.
Highlights
Heart failure is a major cause of mortality worldwide with a 46% projected increase in prevalence by 2030 [1]
We identified several fibroblast growth factor (FGF) proteins that stimulated proliferation of human cardiac progenitor cells, and two of the identified proteins belong to the FGF9 subfamily, which is suggested to be involved in cardiac repair [18]
FGF9, FGF16, and 10 Additional Secreted Proteins Identified to Stimulate Cardiac progenitor cells (CPCs) Proliferation in a Phenotypic Screen
Summary
Heart failure is a major cause of mortality worldwide with a 46% projected increase in prevalence by 2030 [1]. The available therapies for these patients are symptomatic and can only slow down disease progression and reverse limited aspects of cardiac dysfunction. Lower vertebrate species such as zebrafish and newts can regenerate new cardiac tissue after an injury, which was shown in rodent neonatal heart [2,3,4]. Since cardiomyocytes in the adult mammalian heart have limited regenerative capacity (< 1%), different strategies are being investigated to promote cardiac repair. This includes cell therapy using pluripotent stem cells, administration of exogenous paracrine factors in the form of recombinant proteins or modified messenger RNA, and other modalities to stimulate cardiomyocyte proliferation, progenitor cell proliferation, and angiogenesis (for a review, see References [5,6,7,8,9])
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