The effects of glomerular and tubular renal progenitors and derived extracellular vesicles on recovery from acute kidney injury

Andrea Ranghino; Stefania Bruno; Benedetta Bussolati; Aldo Moggio; Veronica Dimuccio; Marta Tapparo; Luigi Biancone; Paolo Gontero; Bruno Frea; Giovanni Camussi

doi:10.1186/s13287-017-0478-5

The effects of glomerular and tubular renal progenitors and derived extracellular vesicles on recovery from acute kidney injury

Stem Cell Res Ther. 2017 Feb 7;8(1):24. doi: 10.1186/s13287-017-0478-5.

Authors

Affiliations

¹ Department of Medical Sciences and Molecular Biotechnology Center, University of Torino, Corso Dogliotti 14, Torino, 10126, Italy. andrea.ranghino@unito.it.
² Department of Molecular Biotechnology and Health Sciences and Molecular Biotechnology Center, University of Torino, Torino, Italy.
³ Department of Medical Sciences and Molecular Biotechnology Center, University of Torino, Corso Dogliotti 14, Torino, 10126, Italy.
⁴ Department of Surgical Sciences, Città della Salute e della Scienza, University of Turin, Torino, Italy.

Abstract

Background: 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).

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Extracellular vesicles; Glomerular mesenchymal stromal cells; Ischemia-reperfusion injury; Renal regeneration.

MeSH terms

AC133 Antigen / genetics
AC133 Antigen / metabolism
Acute Kidney Injury / genetics
Acute Kidney Injury / metabolism
Acute Kidney Injury / pathology
Acute Kidney Injury / therapy*
Animals
Extracellular Vesicles / chemistry
Extracellular Vesicles / transplantation*
Humans
Kidney Glomerulus / metabolism
Kidney Glomerulus / pathology
Kidney Tubules / metabolism
Kidney Tubules / pathology
Male
Mesenchymal Stem Cell Transplantation*
Mesenchymal Stem Cells / cytology*
Mesenchymal Stem Cells / physiology
Mice
Mice, SCID
MicroRNAs / genetics
MicroRNAs / metabolism
Recovery of Function / physiology*
Reperfusion Injury / genetics
Reperfusion Injury / metabolism
Reperfusion Injury / pathology
Reperfusion Injury / therapy*
Transplantation, Heterologous
Transplantation, Homologous
Treatment Outcome

Substances

AC133 Antigen
MicroRNAs
PROM1 protein, human