Pharmacological tools to mobilise mesenchymal stromal cells into the blood promote bone formation after surgery

Tariq G Fellous,Paula Urquhart,Dominique Bonnet,Daniel R Possley,Samantha E Hartner,Mackenzie M Fleischer,Moïra François,Anna Nicolaou,Sara M Rankin,Michael D Newton,Kate H C Gowers,Andia N Redpath,Suet-Ping Wong,Adam M Fahs,Sapan Gandhi,Kevin C Baker

doi:10.1038/s41536-020-0088-1

Abstract

Therapeutic approaches requiring the intravenous injection of autologous or allogeneic mesenchymal stromal cells (MSCs) are currently being evaluated for treatment of a range of diseases, including orthopaedic injuries. An alternative approach would be to mobilise endogenous MSCs into the blood, thereby reducing costs and obviating regulatory and technical hurdles associated with development of cell therapies. However, pharmacological tools for MSC mobilisation are currently lacking. Here we show that β3 adrenergic agonists (β3AR) in combination with a CXCR4 antagonist, AMD3100/Plerixafor, can mobilise MSCs into the blood in mice and rats. Mechanistically we show that reversal of the CXCL12 gradient across the bone marrow endothelium and local generation of endocannabinoids may both play a role in this process. Using a spine fusion model we provide evidence that this pharmacological strategy for MSC mobilisation enhances bone formation.

Highlights

A plethora of studies have reported that mesenchymal stromal cells (MSCs) exhibit regenerative properties in a range of pre-clinical models of disease, including orthopaedic injuries.[1]
A limited number of studies have explored whether MSCs, can— to haematopoietic stem and progenitor cells (HSPCs)—be mobilised from the bone marrow into the blood
An increase in circulating MSCs has been reported in animal models of injury, and high-mobility group protein B1 (HMGB1) and substance P have been identified as the factors that mediate this response.[3,4,5,6]

Summary

Introduction

A plethora of studies have reported that MSCs exhibit regenerative properties in a range of pre-clinical models of disease, including orthopaedic injuries.[1] many clinical trials are underway using culture-expanded MSCs as cell therapies injected intravenously or directly to the site of injury to promote tissue regeneration.[2] In this context MSCs are thought to work primarily through release of paracrine regenerative factors, as MSCs do not appear to permanently integrate into damaged tissues. A limited number of studies have explored whether MSCs, can— to haematopoietic stem and progenitor cells (HSPCs)—be mobilised from the bone marrow into the blood.

Methods

Results

Conclusion