TY - JOUR
T1 - Amniotic membrane-mesenchymal stromal cells secreted factors and extracellular vesicle-miRNAs
T2 - Anti-inflammatory and regenerative features for musculoskeletal tissues
AU - Ragni, Enrico
AU - Papait, Andrea
AU - Perucca Orfei, Carlotta
AU - Silini, Antonietta Rosa
AU - Colombini, Alessandra
AU - Viganò, Marco
AU - Libonati, Francesca
AU - Parolini, Ornella
AU - de Girolamo, Laura
N1 - Funding Information:
PRIN 2017 program of Italian Ministry of Research and University (MIUR), Grant/Award Number: 2017RSAFK7 to Ornella Parolini; Intramural funds from the Università Cattolica del Sacro Cuore, Grant/Award Numbers: Linea D1‐2019, Linea D1‐2018; Italian Ministry of Health, MIUR (5x1000 year 2017); Fondazione Poliambulanza of Brescia; Italian Ministry of Health, “Ricerca Corrente” Funding information
Publisher Copyright:
© 2021 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Press.
PY - 2021/7
Y1 - 2021/7
N2 - Human amniotic membrane-derived mesenchymal stromal cells (hAMSCs) are easily obtained in large quantities and free from ethical concerns. Promising therapeutic results for both hAMSCs and their secreted factors (secretome) were described by several in vitro and preclinical studies, often for treatment of orthopedic disorders such as osteoarthritis (OA) and tendinopathy. For clinical translation of the hAMSC secretome as cell-free therapy, a detailed characterization of hAMSC-secreted factors is mandatory. Herein, we tested the presence of 200 secreted factors and 754 miRNAs in extracellular vesicles (EVs). Thirty-seven cytokines/chemokines were identified at varying abundance, some of which involved in both chemotaxis and homeostasis of inflammatory cells and in positive remodeling of extracellular matrix, often damaged in tendinopathy and OA. We also found 336 EV-miRNAs, 51 of which accounted for more than 95% of the genetic message. A focused analysis based on miRNAs related to OA and tendinopathy showed that most abundant EV-miRNAs are teno- and chondro-protective, able to induce M2 macrophage polarization, inhibit inflammatory T cells, and promote Treg. Functional analysis on IL-1β treated tenocytes and chondrocytes resulted in downregulation of inflammation-associated genes. Overall, presence of key regulatory molecules and miRNAs explain the promising therapeutic results of hAMSCs and their secretome for treatment of musculoskeletal conditions and are a groundwork for similar studies in other pathologies. Furthermore, identified molecules will pave the way for future studies aimed at more sharply predicting disease-targeted clinical efficacy, as well as setting up potency and release assays to fingerprint clinical-grade batches of whole secretome or purified components.
AB - Human amniotic membrane-derived mesenchymal stromal cells (hAMSCs) are easily obtained in large quantities and free from ethical concerns. Promising therapeutic results for both hAMSCs and their secreted factors (secretome) were described by several in vitro and preclinical studies, often for treatment of orthopedic disorders such as osteoarthritis (OA) and tendinopathy. For clinical translation of the hAMSC secretome as cell-free therapy, a detailed characterization of hAMSC-secreted factors is mandatory. Herein, we tested the presence of 200 secreted factors and 754 miRNAs in extracellular vesicles (EVs). Thirty-seven cytokines/chemokines were identified at varying abundance, some of which involved in both chemotaxis and homeostasis of inflammatory cells and in positive remodeling of extracellular matrix, often damaged in tendinopathy and OA. We also found 336 EV-miRNAs, 51 of which accounted for more than 95% of the genetic message. A focused analysis based on miRNAs related to OA and tendinopathy showed that most abundant EV-miRNAs are teno- and chondro-protective, able to induce M2 macrophage polarization, inhibit inflammatory T cells, and promote Treg. Functional analysis on IL-1β treated tenocytes and chondrocytes resulted in downregulation of inflammation-associated genes. Overall, presence of key regulatory molecules and miRNAs explain the promising therapeutic results of hAMSCs and their secretome for treatment of musculoskeletal conditions and are a groundwork for similar studies in other pathologies. Furthermore, identified molecules will pave the way for future studies aimed at more sharply predicting disease-targeted clinical efficacy, as well as setting up potency and release assays to fingerprint clinical-grade batches of whole secretome or purified components.
KW - amnion
KW - extracellular vesicles
KW - inflammation
KW - mesenchymal stem/stromal cells
KW - osteoarthritis
KW - tendinopathy
UR - http://www.scopus.com/inward/record.url?scp=85101905175&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85101905175&partnerID=8YFLogxK
U2 - 10.1002/sctm.20-0390
DO - 10.1002/sctm.20-0390
M3 - Article
C2 - 33656805
AN - SCOPUS:85101905175
VL - 10
SP - 1044
EP - 1062
JO - Stem cells translational medicine
JF - Stem cells translational medicine
SN - 2157-6564
IS - 7
ER -