Recruitment of endogenous stem cells for tissue repair.

The traditional concept of stem cell therapy envisions the isolation of stem cells from patients, propagation and differentiation in vitro, and subsequent re-injection of autologous cells into the patient. There are many problems associated with this paradigm, particularly during the in vitro manipulation process and the delivery and local retention of re-injected cells. An alternative paradigm that could be easier, safer, and more efficient, would involve attracting endogenous stem cells and precursor cells to the defect site for new tissue regeneration. Hepatocyte growth factor (HGF), a pleiotropic cytokine of mesenchymal origin, exerts a strong chemoattractive effect on mesenchymal stem cells (MSCs) and neural stem cells (NSCs), and induces migration of MSCs in vitro. However, HGF undergoes rapid proteolysis in vivo, which results in a very short lifetime of the bioactive cytokine. To maintain the therapeutic level of HGF at the defect site necessary for endogenous stem cell recruitment, sustained, long-term, and localized delivery of HGF is required. Thiol-modified glycosaminoglycans hyaluronan (HA) and heparin (HP), combined with modified gelatin (Gtn), have been crosslinked with poly(ethylene glycol) diacrylate (PEGDA) to afford semisynthetic ECM-like (sECM) hydrogels that can both provide controlled growth factor release and permit cell infiltration and proliferation. Herein we compare the use of different sECM compositions for controlled release of HGF and concomitant recruitment of human bone marrow MSCs into the scaffold in vitro. [Figure: see text].