Abstract
Secretome derived from human amniotic fluid stem cells (AFSC-S) is rich in soluble bioactive factors (SBF) and offers untapped therapeutic potential for regenerative medicine while avoiding putative cell-related complications. Characterization and optimal generation of AFSC-S remains challenging. We hypothesized that modulation of oxygen conditions during AFSC-S generation enriches SBF and confers enhanced regenerative and cardioprotective effects on cardiovascular cells. We collected secretome at 6-hourly intervals up to 30 h following incubation of AFSC in normoxic (21%O2, nAFSC-S) and hypoxic (1%O2, hAFSC-S) conditions. Proliferation of human adult cardiomyocytes (hCM) and umbilical cord endothelial cells (HUVEC) incubated with nAFSC-S or hAFSC-S were examined following culture in normoxia or hypoxia. Lower AFSC counts and richer protein content in AFSC-S were observed in hypoxia. Characterization of AFSC-S by multiplex immunoassay showed higher concentrations of pro-angiogenic and anti-inflammatory SBF. hCM demonstrated highest proliferation with 30h-hAFSC-S in hypoxic culture. The cardioprotective potential of concentrated 30h-hAFSC-S treatment was demonstrated in a myocardial ischemia–reperfusion injury mouse model by infarct size and cell apoptosis reduction and cell proliferation increase when compared to saline treatment controls. Thus, we project that hypoxic-generated AFSC-S, with higher pro-angiogenic and anti-inflammatory SBF, can be harnessed and refined for tailored regenerative applications in ischemic cardiovascular disease.
Highlights
Secretome derived from human amniotic fluid stem cells (AFSC-S) is rich in soluble bioactive factors (SBF) and offers untapped therapeutic potential for regenerative medicine while avoiding putative cell-related complications
AFSC clones were generated from primary amniotic fluid cell culture
As reported in our previous studies, clonal AFSC lines derived with the starter cell method showed stable characteristics between lines[11]
Summary
Secretome derived from human amniotic fluid stem cells (AFSC-S) is rich in soluble bioactive factors (SBF) and offers untapped therapeutic potential for regenerative medicine while avoiding putative cell-related complications. There is speculation that many beneficial effects of stem cell transplantation are due to their modulatory paracrine effects and not directly from transplanted c ells[7] Such results have led to a significant paradigm shift, from exploring stem cell differentiation and tissue regeneration to exploitation of soluble bioactive factors (SBF), characterized as the stem cell secretome (SCS), for functional tissue r ecovery[9]. Oxygen modulation is an effective physical method to achieve this, and the effectiveness of hypoxic induction with several stem cell types is well documented[20,23,24] Such results are encouraging and suggest that SBF concentrations in SCS may be modified for individualized applications. We investigate qualitative and temporal SBF expression in AFSC-S generated in hypoxic and normoxic conditions, its dose-dependent influence on cell proliferation in physiological and ischemic conditions, and its potential in vivo cardioprotective effects in an ischemia/reperfusion (IR) injury animal model
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