Short lifespan of syngeneic transplanted MSC is a consequence of in vivo apoptosis and immune cell recruitment in mice

Mihai Bogdan Preda,Ana-Maria Vacaru,Maya Simionescu,Alexandrina Burlacu,Ioana Madalina Fenyo,Mihai Alin Publik,Carmen Alexandra Neculachi

doi:10.1038/s41419-021-03839-w

Abstract

Mesenchymal stromal cells (MSC) are attractive tools for cell-based therapy, yet the mechanisms underlying their migration and survival post-transplantation are unclear. Accumulating evidence indicates that MSC apoptosis modulates both innate and adaptive immune responses which impact on MSC therapeutic effects. Using a dual tracking system, namely the Luciferase expression and VivoTrack680 labelling, and in vivo optical imaging, we investigated the survival and migration of MSC transplanted by various routes (intravenous, subcutaneous, intrapancreatic and intrasplenic) in order to identify the best delivery approach that provides an accumulation of therapeutic cells to the injured pancreas in the non-obese diabetic (NOD) mouse. The results showed that transplanted MSC had limited migration capacity, irrespective of the administration route, and were short-lived with almost total disappearance at 7 days after transplantation. Within one day after transplantation, cells activated hypoxia signalling pathways, followed by Caspase 3-mediated apoptosis. These were subsequently followed by local recruitment of immune cells at the transplantation site, and the engulfment of apoptotic MSC by macrophages. Our results argue for a “hit and die” mechanism of transplanted MSC. Further investigations will elucidate the molecular crosstalk between the inoculated and the host-immune cells.

Highlights

Mesenchymal stromal cells (MSC) have potent immunomodulatory properties, making these cells rational candidates for the treatment of autoimmune diabetes and other immune disorders[1,2]
MSC survival and migration in non-obese diabetic (NOD) mice Therapeutic attempts for diabetes using MSC raised the question about the potential of these cells to migrate to the inflamed pancreatic islets
Since the Luc expression used in our experimental model was driven by the promoter of phosphoglycerate kinase (Pgk), previously reported to be activated by low oxygen concentrations[24], we evaluated whether the Luc signal was affected by hypoxia and/

Summary

Introduction

Mesenchymal stromal cells (MSC) have potent immunomodulatory properties, making these cells rational candidates for the treatment of autoimmune diabetes and other immune disorders[1,2]. The implementation of MSC-based therapies still imposes numerous considerations that impact the clinical outcome, including the route of administration, the fate of cells after transplantation, the pharmacokinetics and biological properties of the transplanted MSC3. Accumulating evidence indicates that in vivo apoptosis affects the transplanted cells and this process could impact the mechanism of MSC-mediated immunosuppression. The “dying stem cell hypothesis”, by which the apoptosis of transplanted MSC modulates the innate and adaptive immune responses, was first formulated in 2005 Several studies suggested that local or systemic administration of MSC prevented the onset of diabetes and reversed

Methods

Results

Conclusion