Methods for restoration of diabetic bone marrow cell function for cell based therapy, using pre-existing molecules and their derivatives.
- Ability to "reactivate" diabetic bone marrow-derived stem or progenitor cells which also include peripheral blood cells such as endothelial progenitor cells.
- Cells are more angiogenic and effective due to extensive gene silencing at key sites from endothelial progenitor cells.
- Some derivatives show enhanced activity and reduced toxicity over pre-existing molecules.
Approximately 26 million adults and children in the United States have been diagnosed with diabetes. The reprogramming of stem or progenitor cells from diabetic patients enables the use of multiple cell-based therapy applications amongst the diabetic population. Primary targets for cell-based therapies (stem or progenitor cells) include cardiovascular disease and stroke, which are the leading cause of death and disability among people with diabetes; approximately 65% of diabetics die from some form of heart disease or stroke. Cell-based therapies also target neurodegenerative diseases, which affect approximately 20% of diabetics and represent the greatest source of morbidity amongst diabetic patients. Other targets for cell-based therapy include musculoskeletal disorders, such as carpal tunnel syndrome and adhesive capsulitis, which affect up to 20% of diabetics, as well as major trauma and spinal cord injury.
Various cells derived from bone marrow can be used in cell therapy for multiple diseases. However, stem or progenitor cells isolated from diabetic patients exhibit reduced cellular activity due to epigenetic changes which precludes their use in cell therapy. Researchers at Emory University have developed a system to identify angiogenic and paracrine genes that are affected by epigenetic changes in diabetic bone marrow-derived stem or progenitor cells using standard gene array technology. This system can reverse these changes by selective treatment with known small molecules to rescue the phenotype of "normal" stem or progenitor cells. Using their protocol, the investigators identified a range of known small molecule regulators with high functionality. In addition, a range of derivate molecules were developed, to reduce toxicity and enhance potency in vivo. These regulators were then used successfully to confirm the rescue of the "normal" phenotype in vitro. These molecules have potential as a unified treatment for the underlying cause of all microvascular complications, as well as a treatment for diabetic neuropathy that offers not only symptomatic relief, but also delays or potentially stops the progression of the disease.
Method was used to identify small molecule regulators that rescued the normal phenotype in bone marrow cells isolated from diabetic rats and human patients.
Publication: Zhu et al., 2010. Cell Stem Cell. Volume 7, Issue 6, 651-655, 3 December 2010