Poor Cell Survival Limits the Beneficial Impact of Mesenchymal Stem Cell Transplantation on Acute Kidney Injury

Abstract

Background: Although renal tubular epithelium has a great capacity for repair it has been suggested that the administration of mesenchymal stem cells may accelerate the recovery following severe ischemic injury. Methods: Here we analyzed the survival rate and organ distribution of transplanted mesenchymal stem cells as well as their contribution to kidney regeneration after ischemic renal injury using functional tests, histological examination as well as quantitative real-time PCR. Results: Intravenously injected stem cells were mainly trapped in lungs and liver. One hour after injection, less than 1% of the injected stem cells could be detected in the injured kidneys. These cells disappeared within the first few days and did not replace renal epithelial cells precluding substantial transdifferentiation. To clarify whether reinforced stem cell delivery might promote sustained survival or conversion to tubular epithelia, stem cells were directly injected into the injured kidneys. Although these grafted cells also did not show sustained survival or contribute to structural renal repair, stem cell injection was associated with a significant but transient initial decrease in serum creatinine. Conclusion: These data suggest that mesenchymal stem cells do not significantly contribute to epithelial renewal after ischemic injury, promoting the idea that the major impact of cell-based therapy for acute kidney injury may result from paracrine or endocrine effects unrelated to stem cell transdifferentiation.

Initial steps to stabilize the microenvironment for implantation of stem/progenitor cells in diseased renal parenchyma

“…However, critical reading of related literature also elucidates that this innovative therapeutic approach is still in a phase of basic research, since survival of implanted stem/ progenitor cells and initial regeneration is limited [5][6][7]. This fact has several causes.…”

14S,21R-dihydroxy-docosahexaenoic Acid Treatment Enhances Mesenchymal Stem Cell Amelioration of Renal Ischemia/Reperfusion Injury

“…The low viability of transplanted MSCs in I/R injured organs remains an important limitation for MSC therapy [2,27]. The enhancement of MSC renotrophic functions after 14S,21R-diHDHA treatment is likely mediated in part by the promotion of MSC survival, as suggested by the reduced rate of apoptosis of MSCs grafted into I/R injured kidneys, an inhospitable environment for MSC survival (Fig.…”

“…A few intravenously infused MSCs are retained in the kidneys [27,42], which makes it difficult to quantitatively study the effects of 14S,21R-diHDHA on MSC apoptosis in kidneys. Therefore, we transplanted MSCs under the kidney capsule following previously reported procedures [43].…”

“…IGF-1 blocks not only the early onset of apoptosis, but also inflammation and accompanying tissue injury [26]. Although MSCs possess the capability to ameliorate acute kidney injury, the low viability of transplanted cells in I/R injured organs remains an important limitation for MSC therapy [2,27]. Reactive oxygen species (ROS) and inflammatory cytokines generated in I/R are the probable source of damage to the grafted MSCs [8,20].…”

Use of mouse hematopoietic stem and progenitor cells to treat acute kidney injury

“…One possible reason behind this phenomenon is low viability of treated cells once localized to the tissue. This could be analogous to intravenously injected MSC that have been shown to be trapped mainly in the liver and the lungs and have poor survival in these organs (4). Although low survival limits the potential of direct cell replacement for an injured organ, it provides some reassurance in safety of using treated cells for therapy.…”