STEM/PROGENITOR CELL TREATMENTS IN STROKE

Stroke is the leading cause of adult disability. Stem or progenitor transplantation improves recovery in many pre-clinical stroke models. However, stem/progenitor therapies have not been translated to the clinic. At least three limitations have impacted the clinical utility or translation of stem/progenitor cell therapies in stroke: most of the transplanted cells die, the surviving cells often do not differentiate, and the direct injection of transplanted stem cells into the tissue adjacent to the stroke may produce damage at this site, which is the region of most repair and recovery in this disease. These limitations have established a translational bottleneck in stroke therapy. Tissue bioengineering approaches provide a possible solution to these problems. Work with self-assembling biopolymers or nanosystems provides an ability to link functionally important molecules for stem cell survival, such as extracellular matrix proteins, to stem cell or progenitor preparations within a pro-survival or pro-growth matrix. We have shown that such a preparation, a biopolymer hydrogel, allows stem cells to be transplanted directly into the stroke cavity. The stroke cavity is normally a hostile site for stem cell transplantation. It is avascular and inflamed, and most transplanted cells die when placed into this site. Yet, it is an ideal site for stem cell transplantation in stroke.  It is a cavity and can accept a large volume transplant, and it is directly adjacent to, and can interact with, a major site of neural repair in stroke, the peri-infarct tissue. We have utilized hydrogels with extracellular matrix proteins as a matrix to support stem/progenitor transplantation into the stroke cavity after stroke (Zhong et al.).  This matrix improves transplant survival and diminishes inflammatory attach on the transplant site.

Stem/progenitor transplant into stroke. Inflammation Stem Cells Stroke HydrogelMouse neuronal precursor cells were transplanted into the stroke cavity 7 days after stroke in a mouse stroke model. These cells were labeled with a lentivirus coding for green fluorescent protein.  Microglia and macrophages were labeled with IBA-1 (red). These inflammatory cells infiltrate the transplant site in the control transplant condition (without hydrogel) left column, but are less numerous in when the neuronal precursor cells are transplanted within the hydrogel (right column).

 

Current studies in the Carmichael lab are using tissue bioengineering approaches to develop a novel stem cell therapy for stroke neural repair. A focus of these studies is on developing a hydrogel with tunable properties that incorporates extracellular matrix protein motifs to promote survival and/or differentiation of co-injected stem/progenitor cells into the stroke cavity.