Bioactivity and miRNome Profiling of Native Extracellular Vesicles in Human Induced Pluripotent Stem Cell‐Cardiomyocyte Differentiation. Issue 15 (24th March 2022)

• Record Type: Journal Article
• Authors: Louro, Ana F.; Paiva, Marta A.; Oliveira, Marta R.; Kasper, Katharina A.; Alves, Paula M.; Gomes‐Alves, Patrícia; Serra, Margarida
• Is Part Of: Advanced science. Volume 9:Issue 15(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-03-24
• Subjects: cardiac regeneration -- cell biofactory -- extracellular vesicles -- miRNome -- small RNA‐seq; Science -- Periodicals; 505
• DOI: 10.1002/advs.202104296
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: Extracellular vesicles (EV) are an attractive therapy to boost cardiac regeneration. Nevertheless, identification of native EV and corresponding cell platform(s) suitable for therapeutic application, is still a challenge. Here, EV are isolated from key stages of the human induced pluripotent stem cell‐cardiomyocyte (hiPSC‐CM) differentiation and maturation, i.e., from hiPSC (hiPSC‐EV), cardiac progenitors, immature and mature cardiomyocytes, with the aim of identifying a promising cell biofactory for EV production, and pinpoint the genetic signatures of bioactive EV. EV secreted by hiPSC and cardiac derivatives show a typical size distribution profile and the expression of specific EV markers. Bioactivity assays show increased tube formation and migration in HUVEC treated with hiPSC‐EV compared to EV from committed cell populations. hiPSC‐EV also significantly increase cell cycle activity of hiPSC‐CM. Global miRNA expression profiles, obtained by small RNA‐seq analysis, corroborate an EV‐miRNA pattern indicative of stem cell to cardiomyocyte specification, confirming that hiPSC‐EV are enriched in pluripotency‐associated miRNA with higher in vitro pro‐angiogenic and pro‐proliferative properties. In particular, a stemness maintenance miRNA cluster upregulated in hiPSC‐EV targets the PTEN/PI3K/AKT pathway, involved in cell proliferation and survival. Overall, the findings validate hiPSC as cell biofactories for EV production for cardiac regenerative applications. Abstract : Extracellular vesicles (EV) from key stages of the hiPSC‐cardiomyocyte differentiation and maturation are characterized, and EV bioactivity, particularly for native hiPSC‐EV, is shown. These EV are enriched in stemness maintenance miRNA, predicted to target the PI3K/AKT pathway, intrinsically involved in cell survival and proliferation. The potential of hiPSC as cell biofactories for the production of therapeutic EV is validated.