Open AccessBioactivity and miRNome Profiling of Native Extracellular Vesicles in Human Induced Pluripotent Stem Cell‐Cardiomyocyte Differentiation
Author(s) -
Louro Ana F.,
Paiva Marta A.,
Oliveira Marta R.,
Kasper Katharina A.,
Alves Paula M.,
GomesAlves Patrícia,
Serra Margarida
Publication year - 2022
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202104296
Subject(s) - microbiology and biotechnology , induced pluripotent stem cell , cell growth , stem cell , microrna , biology , extracellular vesicle , cell , cellular differentiation , chemistry , progenitor cell , pi3k/akt/mtor pathway , downregulation and upregulation , signal transduction , microvesicles , genetics , gene , embryonic stem cell
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.