Pharmacological Mobilization of Progenitor Cells for Tissue Regeneration. (360G-Wellcome-095700_Z_11_Z)

My vision is to accelerate early stage research elucidating the molecular mechanisms regulating the mobilization of endogenous non-haematological stem cells from the bone marrow that will translate into development of innovative regenerative medicines. It has been known for many years that the cytokine G-CSF stimulates the mobilization of haematopoietic stem cells (HSCs) from the bone marrow into the blood. This knowledge has been applied clinically for the mobilization of HSCs for bone marrow transplants. Moreover, the molecular mechanisms regulating HSC mobilization have been studied extensively in the quest to identify more efficacious mobilizing regimens(1). A major breakthrough in this respect was the discovery that the CXCR4/CXCL12 chemokine axis plays a critical role in the retention of HSCs in the bone marrow, which led to the development of CXCR4 antagonists as potent mobilizing drugs (Figure 1 and 2) (1,2). Non-haematological stem cells residing in the adult bone marrow in clude the multipotent mesenchymal stromal cells (MSCs), a heterogeneous population of cells that have the capacity to differentiate into cells of the mesenchymal lineage including chondrocytes, osteoblasts and muscle and also to modulate the immune system(3-5).MSCs are currently being evaluated in animal models and clinical trials for their capacity to promote tissue regeneration, for example following myocardial infarction or in the context of orthopaedic injuries and for the treatment of autoi mmune diseases, such as acute graft versus host disease (acute GvHD)(3-5). Many studies have shown that MSCs delivered intravenously home to areas of tissue injury or inflammation and are effective in promoting tissue regeneration or immunosuppression(3-5). Current therapeutic use of MSCs relies on their ex vivo expansion and is, therefore, associated with regulatory and technical hurdles. I have discovered a pharmacological regimen for the mobilization of endogenous MSCs from the bone marrow in to the blood(6). Such a therapy provides a cost effective, innovative approach to regenerative medicine, circumventing problems classically associated with stem cell therapy. Stem cell mobilization cannot be accurately measured by simply determining stem cell numbers in the blood, due to the propensity of mobilized stem cells to rapidly home back to the bone marrow and other tissues. Indeed some studies have shown that HSC mobilization may be masked by rapid homing of HSCs back to the bone marr ow(7). I have pioneered an innovative approach to study mobilization that circumvents these problems(6,8-12). The technique requires microsurgery to cannulate the vasculature of the femoral bone marrow in situ in an anaesthetised mouse. In this perfusion system mobilizing factors can be infused directly into the bone marrow vasculature via cannulation of the femoral artery while mobilized stem cells are collected by cannulation of the femoral vein. Using this unique system I have been able to show, for the first time, that different populations of stem cells can be selectively mobilized pharmacologically from the bone marrow(6). Specifically, I have discovered that VEGF-A pre-treatment of mice prevents HSC mobilization by the CXCR4 antagonist, while promoting