Combining transfusion of stem/progenitor cells into the peripheral circulation with localized transplantation in situ at the site of tissue/organ damage: A possible strategy to optimize the efficacy of stem cell transplantation therapy

Summary Several studies have demonstrated the efficacy of localized in situ transplantation of stem/progenitor cells for tissue/organ regeneration. However, the possible limitations of such an approach have largely been overlooked. This is contrary to the intrinsic physiological process of tissue/organ regeneration in vivo, which is thought to involve the mobilization of stem/progenitor cells resident within the tissue/organ itself, as well as from ectopic sites, in particular the bone marrow. Signaling pathways and other molecular processes within stem/progenitor cells transplanted in situ may not be primed to achieve optimal tissue/organ regeneration, and may even be confused by the sudden rapid transition in the cellular microenvironment encountered during transplantation. To overcome these putative limitations, a possible strategy may be to combine transfusion of stem/progenitor cells into the peripheral circulation with localized transplantation in situ at the site of tissue/organ damage. This could better replicate the natural physiological process of tissue/organ repair in vivo. Possible synergistic interactions between the transplanted stem/progenitor cells in situ with migratory transfused cells from the peripheral circulation may further enhance tissue/organ regeneration. The transfused stem/progenitor cells may be induced to home in on a damaged tissue/organ, via the controlled release of specific cytokines or chemokines (i.e., SDF-1) emanating from that particular tissue/organ. There are a number of possible ways to achieve this. For example, the transplanted cells may be delivered on tissue-engineered scaffolds that are designed for the controlled release of specific homing factors such as SDF-1. Another alternative may be to stimulate or genetically modulate the transplanted cells to copiously secrete homing factors such as SDF-1, to encourage the migration and homing of transfused cells within the peripheral circulation. At the same time, it may also be advantageous to pre-stimulate the transfused cells to strongly express surface receptors specific to homing factors such as SDF-1, in particular CXCR-4. More rigorous investigations should be carried out on the possible strategy of combining in situ transplantation of stem/progenitor cells with transfusion into the peripheral circulation, together with induced homing of the transfused cells to the site of organ/tissue damage. This may possibly result in better efficacy for some, but not all models of tissue/organ regeneration.