Bioluminescence imaging to monitor the in vivo distribution of administered mesenchymal stem cells in acute kidney injury

AKI remains a highly prevalent disease associated with poor short-and long-term outcomes and high costs. Although significant advances in our understanding of repair after AKI have been made over the last 5 years, this knowledge has not yet been translated into new AKI therapies. A consensus conference held by the Acute Dialysis Quality Initiative was convened in April of 2014 and reviewed new evidence on successful kidney repair to identify the most promising pathways that could be translated into new treatments. In this paper, we provide a summary of current knowledge regarding successful kidney repair and offer a framework for conceptualizing the therapeutic targeting that may facilitate this process. We outline gaps in knowledge and suggest a research agenda to more efficiently bring new discoveries regarding repair after AKI to the clinic.

Section: What Aspects Of Repair Can Be Targeted Therapeutically?mentioning

confidence: 99%

Targeting Endogenous Repair Pathways after AKI

Humphreys

Cantaluppi

Portilla

et al. 2016

“…10,11 MSCs were shown to localize within the injured kidneys when injected in mice with AKI. 3,5,6,12 However, several reports indicate only a transient recruitment of MSCs in the renal vasculature without a direct incorporation within the regenerating tubules. 7,8,13 It was suggested that the transient presence of MSCs within the injured kidney may provide a paracrine support to the repair, which is mainly sustained by intrinsic epithelial cells surviving injury.…”

mentioning

confidence: 99%

Mesenchymal Stem Cell-Derived Microvesicles Protect Against Acute Tubular Injury

Bruno¹,

Grange²,

Deregibus³

et al. 2009

1,152

1,173

Administration of mesenchymal stem cells (MSCs) improves the recovery from acute kidney injury (AKI).The mechanism may involve paracrine factors promoting proliferation of surviving intrinsic epithelial cells, but these factors remain unknown. In the current study, we found that microvesicles derived from human bone marrow MSCs stimulated proliferation in vitro and conferred resistance of tubular epithelial cells to apoptosis. The biologic action of microvesicles required their CD44-and ␤1-integrin-dependent incorporation into tubular cells. In vivo, microvesicles accelerated the morphologic and functional recovery of glycerol-induced AKI in SCID mice by inducing proliferation of tubular cells. The effect of microvesicles on the recovery of AKI was similar to the effect of human MSCs. RNase abolished the aforementioned effects of microvesicles in vitro and in vivo, suggesting RNA-dependent biologic effects. Microarray analysis and quantitative real time PCR of microvesicle-RNA extracts indicate that microvesicles shuttle a specific subset of cellular mRNA, such as mRNAs associated with the mesenchymal phenotype and with control of transcription, proliferation, and immunoregulation. These results suggest that microvesicles derived from MSCs may activate a proliferative program in surviving tubular cells after injury via a horizontal transfer of mRNA.

“…The systemic delivery of BM-MSCs after a variety of acute renal injuries (glycerol, mercury chloride, cisplatin, and ischemic injury) elicits a reparative effect in animal models. [8][9][10][11][12][13] Although it was initially thought to occur by the transdifferentiation of MSCs into renal epithelium, 8 the observed improvements in histology and function are now considered to result from the secretion of proreparative factors. 9,12,14,15 Cells with MSC-like properties have now been isolated from many solid organs.…”

mentioning

confidence: 99%

Collecting Duct-Derived Cells Display Mesenchymal Stem Cell Properties and Retain Selective In Vitro and In Vivo Epithelial Capacity

Ariunbold

Suhaimi

et al. 2015

We previously described a mesenchymal stem cell (MSC)-like population within the adult mouse kidney that displays long-term colony-forming efficiency, clonogenicity, immunosuppression, and panmesodermal potential. Although phenotypically similar to bone marrow (BM)-MSCs, kidney MSC-like cells display a distinct expression profile. FACS sorting from Hoxb7/enhanced green fluorescent protein (GFP) mice identified the collecting duct as a source of kidney MSC-like cells, with these cells undergoing an epithelialto-mesenchymal transition to form clonogenic, long-term, self-renewing MSC-like cells. Notably, after extensive passage, kidney MSC-like cells selectively integrated into the aquaporin 2-positive medullary collecting duct when microinjected into the kidneys of neonatal mice. No epithelial integration was observed after injection of BM-MSCs. Indeed, kidney MSC-like cells retained a capacity to form epithelial structures in vitro and in vivo, and conditioned media from these cells supported epithelial repair in vitro. mice revealed evidence for the intercalation of a Wnt4-expressing interstitial population into the neonatal collecting duct, suggesting that such intercalation may represent a normal developmental mechanism giving rise to a distinct collecting duct subpopulation. These results extend previous observations of papillary stem cell activity and collecting duct plasticity and imply a role for such cells in collecting duct formation and, possibly, repair.