TY - JOUR
T1 - Extracellular vesicles released by adipose tissue-derived mesenchymal stromal/stem cells from obese pigs fail to repair the injured kidney
AU - Eirin, Alfonso
AU - Ferguson, Christopher M.
AU - Zhu, Xiang Yang
AU - Saadiq, Ishran M.
AU - Tang, Hui
AU - Lerman, Amir
AU - Lerman, Lilach O.
N1 - Publisher Copyright:
© 2020 The Author(s)
PY - 2020/8
Y1 - 2020/8
N2 - Aims: Mesenchymal stromal/stem cell (MSC)-derived extracellular vesicles (EVs) shuttle select MSC contents and are endowed with an ability to repair ischemic tissues. We hypothesized that exposure to cardiovascular risk factors may alter the microRNA cargo of MSC-derived EVs, blunting their capacity to repair the post-stenotic kidney in pigs with metabolic syndrome (MetS) and renal artery stenosis (RAS). Methods: Porcine MSCs were harvested from abdominal fat after 16wks of Lean- or MetS-diet, and their EVs isolated and characterized using microRNA-sequencing. Lean- and MetS-EV protective effects were assessed in-vitro in human umbilical endothelial cells (HUVECs). To compare their in-vivo efficacy to repair ischemic tissues, allogeneic-EVs were intrarenally delivered in pigs after 6wks of MetS + RAS, and 4wks later, single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were studied in-vivo, and microvascular architecture and injury ex-vivo. Lean-, MetS-, and MetS + RAS-sham served as controls (n = 6 each). Results: Ten microRNAs, capable of targeting several pro-angiogenic genes, were upregulated in MetS-EVs versus Lean-EVs. In vitro, MetS-EVs failed to increase tube number and length, and to boost HUVEC migration compared to Lean-EVs. Lean- and MetS-EVs were detected in the stenotic-kidney 4wks after injection in the vicinity of small vessels. RBF and GFR were lower in MetS + RAS versus MetS, and restored in MetS + RAS + Lean-EVs, but not in MetS + RAS + MetS-EVs. Furthermore, MetS-EVs failed to restore renal expression of angiogenic factors, improve microvascular density, or attenuate fibrosis. Conclusions: MetS alters the microRNA cargo of MSC-derived EVs and impairs their functional potency, limiting the therapeutic efficacy of this endogenous cellular repair system.
AB - Aims: Mesenchymal stromal/stem cell (MSC)-derived extracellular vesicles (EVs) shuttle select MSC contents and are endowed with an ability to repair ischemic tissues. We hypothesized that exposure to cardiovascular risk factors may alter the microRNA cargo of MSC-derived EVs, blunting their capacity to repair the post-stenotic kidney in pigs with metabolic syndrome (MetS) and renal artery stenosis (RAS). Methods: Porcine MSCs were harvested from abdominal fat after 16wks of Lean- or MetS-diet, and their EVs isolated and characterized using microRNA-sequencing. Lean- and MetS-EV protective effects were assessed in-vitro in human umbilical endothelial cells (HUVECs). To compare their in-vivo efficacy to repair ischemic tissues, allogeneic-EVs were intrarenally delivered in pigs after 6wks of MetS + RAS, and 4wks later, single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were studied in-vivo, and microvascular architecture and injury ex-vivo. Lean-, MetS-, and MetS + RAS-sham served as controls (n = 6 each). Results: Ten microRNAs, capable of targeting several pro-angiogenic genes, were upregulated in MetS-EVs versus Lean-EVs. In vitro, MetS-EVs failed to increase tube number and length, and to boost HUVEC migration compared to Lean-EVs. Lean- and MetS-EVs were detected in the stenotic-kidney 4wks after injection in the vicinity of small vessels. RBF and GFR were lower in MetS + RAS versus MetS, and restored in MetS + RAS + Lean-EVs, but not in MetS + RAS + MetS-EVs. Furthermore, MetS-EVs failed to restore renal expression of angiogenic factors, improve microvascular density, or attenuate fibrosis. Conclusions: MetS alters the microRNA cargo of MSC-derived EVs and impairs their functional potency, limiting the therapeutic efficacy of this endogenous cellular repair system.
KW - Metabolic syndrome
KW - MicroRNA
KW - Renovascular disease
KW - Stem cells
UR - http://www.scopus.com/inward/record.url?scp=85086777138&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85086777138&partnerID=8YFLogxK
U2 - 10.1016/j.scr.2020.101877
DO - 10.1016/j.scr.2020.101877
M3 - Article
C2 - 32592955
AN - SCOPUS:85086777138
SN - 1873-5061
VL - 47
JO - Stem Cell Research
JF - Stem Cell Research
M1 - 101877
ER -