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

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.

Autophagy Promotes the Survival of Adipose Mesenchymal Stem/Stromal Cells and Enhances Their Therapeutic Effects in Cisplatin-Induced Liver Injury via Modulating TGF-β1/Smad and PI3K/AKT Signaling Pathways

“…However, one of the chief hurdles for successful MSCs transplantation is the poor survival rate after MSCs settle within the inflamed and hypoxic environments of damaged tissues [15]. As it was previously noted, transplanted MSCs underwent apoptosis post-transplantation in vivo [16]. Nevertheless, recent studies provided evidence that autophagy activation in MSCs directly before their transplantation enhanced their viability, post-transplantation survival, promoted their differentiation, immunomodulation, and pro-angiogenic capabilities, and henceforth, improved the overall tissue repair potential [17].…”

Periodontal Wound Healing and Regeneration: Insights for Engineering New Therapeutic Approaches

“…Variations in scaffold material and design may also have influenced the activity of PDLCs in each of these models. Host immune cells can target both syngeneic and allogeneic transplanted cells for clearance (266,267), and biomaterials can be designed to provide an immunoprotective environment to prolong the survival of transplanted cells (268, 269). Alternatively, inclusion of transplanted cells within scaffolds can favorably alter the immune response to implanted biomaterials, reducing the foreign body reaction (270,271).…”

Mesenchymal Stem Cell-Based Therapy for Rheumatoid Arthritis

“…Similar results were reported by another group. The MCSs effect is based on the hypoxia-induced activation of caspase 3-mediated apoptosis, recruitment of immune cells at the transplantation site and their further engulfment by locally circulating macrophages [ 114 ].…”