Hypoxia-induced amniotic fluid stem cell secretome augments cardiomyocyte proliferation and enhances cardioprotective effects under hypoxic-ischemic conditions

• Published in: Scientific reports Vol. 11; no. 1; pp. 163 - 15
• Main Authors: Kukumberg, Marek, Phermthai, Tatsanee, Wichitwiengrat, Suparat, Wang, Xiaoyuan, Arjunan, Subramanian, Chong, Suet Yen, Fong, Chui-Yee, Wang, Jiong-Wei, Rufaihah, Abdul Jalil, Mattar, Citra Nurfarah Zaini
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/532; 631/532/2064; 692/4019; Amniotic fluid; Amniotic Fluid - cytology; Amniotic Fluid - metabolism; Angiogenesis; Animals; Apoptosis; Cardiomyocytes; Cardiovascular diseases; Cell culture; Cell Differentiation; Cell Hypoxia; Cell Proliferation; Cell size; Cells, Cultured; Endothelial cells; Female; Human Umbilical Vein Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells - metabolism; Humanities and Social Sciences; Humans; Hypoxia; Hypoxia - genetics; Hypoxia - metabolism; Hypoxia - physiopathology; Inflammation; Ischemia; Ischemia - metabolism; Ischemia - physiopathology; Male; Mice; Mice, Inbred C57BL; multidisciplinary; Myocardial ischemia; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Oxygen - metabolism; Protein Translocation Systems - genetics; Protein Translocation Systems - metabolism; Regenerative medicine; Reperfusion; Science; Science (multidisciplinary); Secretome; Stem cell transplantation; Stem cells; Stem Cells - cytology; Stem Cells - metabolism; Umbilical cord
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-80326-w

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%O 2 , nAFSC-S) and hypoxic (1%O 2 , 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.