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Abstract: The potential of collagen scaffolds for promoting angiogenesis/arteriogenesis was studied in vivo by implantation on healthy or cryoinjured left ventricles of rats up to 60 days post-injury. Blood vessels content and extra-vascular cell infiltration were evaluated within the collagen scaffold, the cryoinjured areas, and the “border zones” of the myocardium facing the cryoinjured zones. The collagen cardiac patches were almost completely absorbed in 60 days and became populated by new arterioles and capillaries in both intact and cryoinjured heart (arterioles in cryoinjured vs. intact zones were about 2,3-fold higher; capillaries in cryoinjured vs. intact zones were 1.7-fold higher). Collagen cardiac patches exerted a “trophic” effect on the organizing granulation tissue that emerged from the wound-healing process, increasing vessel density of 2.7-fold for arterioles and 4-fold for capillaries. Interstitial cells in collagen cardiac patches rarely (<1%) expressed cardiogenic stem cells markers such as Sca-1- or MDR1, whereas markers of neural crest cells GFAP+/nestin+ cells ranged from 3/30% to 30/70% in collagen cardiac patches placed on intact vs. cryoinjured heart, respectively. Myofibroblasts and cardiomyocytes (CM) were absent but macrophages populated the collagen scaffolds even after 60 days from implantation. Western blotting of collagen cardiac patches after implantation on intact/cryoinjured hearts confirmed that markers of endothelial and smooth muscle cells, but not of CM, were expressed. The porous collagen scaffold was able to elicit a powerful angiogenetic and arteriogenetic response in the intact and cryoinjured hearts, representing an ideal tool for therapeutic angio-arteriogenesis and a potentially useful substrate for stem cell seeding. [Copyright &y& Elsevier]

The adult mammalian heart retains residual regenerative capability via endogenous cardiac progenitor cell (CPC) activation and cardiomyocyte proliferation. We previously reported the paracrine cardioprotective capacity of human amniotic fluid-derived stem cells (hAFS) following ischemia or cardiotoxicity. Here we analyse the potential of hAFS secretome fractions for cardiac regeneration and future clinical translation. hAFS were isolated from amniotic fluid leftover samples from prenatal screening. hAFS conditioned medium (hAFS-CM) was obtained following hypoxic preconditioning. Anti-apoptotic, angiogenic and proliferative effects were evaluated on rodent neonatal cardiomyocytes (r/mNVCM), human endothelial colony forming cells (hECFC) and human CPC. Mice undergoing myocardial infarction (MI) were treated with hAFS-CM, hAFS-extracellular vesicles (hAFS-EV), or EV-depleted hAFS-CM (hAFS-DM) by single intra-myocardial administration and evaluated in the short and long term. hAFS-CM improved mNVCM survival under oxidative and hypoxic damage, induced Ca2+-dependent angiogenesis in hECFC and triggered hCPC and rNVCM proliferation. hAFS-CM treatment after MI counteracted scarring, supported cardiac function, angiogenesis and cardiomyocyte cell cycle progression in the long term. hAFS-DM had no effect. hAFS-CM and hAFS-EV equally induced epicardium WT1+ CPC reactivation. Although no CPC cardiovascular differentiation was observed, our data suggests contribution to local angiogenesis by paracrine modulation. hAFS-EV alone were able to recapitulate all the beneficial effects exerted by hAFS-CM, except for stimulation of vessel formation. hAFS-CM and hAFS-EV can improve cardiac repair and trigger cardiac regeneration via paracrine modulation of endogenous mechanisms. While both formulations are effective in sustaining myocardial renewal, hAFS-CM retains higher pro-angiogenic potential, while hAFS-EV particularly enhances cardiac function. Unlabelled Image • The hAFS secretome improves cardiac repair in the long term after a single intra-myocardial injection. • The hAFS secretome can efficiently restore endogenous epicardial progenitors activation. • The hAFS secretome can sustain cardiomyocyte cell cycle re-entry after injury. • Extracellular vesicles from the hAFS secretome recapitulate most of its paracrine effects, but for new vessel stimulation. • The hAFS secretome might represent a promising pharmacotherapeutic agent against cardiovascular disease. [ABSTRACT FROM AUTHOR]