The effects of glomerular and tubular renal progenitors and derived extracellular vesicles on recovery from acute kidney injury.
Mesenchymal stromal cells (MSCs) and renal stem/progenitors improve the recovery of acute kidney injury (AKI) mainly through the release of paracrine mediators including the extracellular vesicles (EVs). Several studies have reported the existence of a resident population of MSCs within the glomeruli (Gl-MSCs). However, their contribution towards kidney repair still remains to be elucidated. The aim of the present study was to evaluate whether Gl-MSCs and Gl-MSC-EVs promote the recovery of AKI induced by ischemia-reperfusion injury (IRI) in SCID mice. Moreover, the effects of Gl-MSCs and Gl-MSC-EVs were compared with those of CD133+progenitor cells isolated from human tubules of the renal cortical tissue (T-CD133+cells) and their EVs (T-CD133+-EVs).



IRI was performed in mice by clamping the left renal pedicle for 35 minutes together with a right nephrectomy. Immediately after reperfusion, the animals were divided in different groups to be treated with: Gl-MSCs, T-CD133+cells, Gl-MSC-EVs, T-CD133+-EVs or vehicle. To assess the role of vesicular RNA, EVs were either isolated by floating to avoid contamination of non-vesicles-associated RNA or treated with a high dose of RNase. Mice were sacrificed 48 hours after surgery.



Gl-MSCs, and Gl-MSC-EVs both ameliorate kidney function and reduce the ischemic damage post IRI by activating tubular epithelial cell proliferation. Furthermore, T-CD133+cells, but not their EVs, also significantly contributed to the renal recovery after IRI compared to the controls. Floating EVs were effective while RNase-inactivated EVs were ineffective. Analysis of the EV miRnome revealed that Gl-MSC-EVs selectively expressed a group of miRNAs, compared to EVs derived from fibroblasts, which were biologically ineffective in IRI.



In this study, we demonstrate that Gl-MSCs may contribute in the recovery of mice with AKI induced by IRI primarily through the release of EVs.
Department of Medical Sciences and Molecular Biotechnology Center, University of Torino, Corso Dogliotti 14, Torino, 10126, Italy. andrea.ranghino@unito.it.
Andrea
A
Ranghino
Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Torino, Torino, Italy.
Stefania
S
Bruno
Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Torino, Torino, Italy.
Benedetta
B
Bussolati
Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Torino, Torino, Italy.
Aldo
A
Moggio
Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Torino, Torino, Italy.
Veronica
V
Dimuccio
Department of Medical Sciences and Molecular Biotechnology Center, University of Torino, Corso Dogliotti 14, Torino, 10126, Italy.
Marta
M
Tapparo
Department of Medical Sciences and Molecular Biotechnology Center, University of Torino, Corso Dogliotti 14, Torino, 10126, Italy.
Luigi
L
Biancone
Department of Surgical Sciences, Città della Salute e della Scienza, University of Turin, Torino, Italy.
Paolo
P
Gontero
Department of Surgical Sciences, Città della Salute e della Scienza, University of Turin, Torino, Italy.
Bruno
B
Frea
Department of Medical Sciences and Molecular Biotechnology Center, University of Torino, Corso Dogliotti 14, Torino, 10126, Italy.
Giovanni
G
Camussi
D000071916:AC133 Antigen / Q000235:genetics / Q000378:metabolism; D058186:Acute Kidney Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000067128:Extracellular Vesicles / Q000737:chemistry / Q000637:transplantation*; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology*; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D000071916:AC133 Antigen; D035683:MicroRNAs; C000606023:PROM1 protein, human
Extracellular vesicles; Glomerular mesenchymal stromal cells; Ischemia-reperfusion injury; Renal regeneration