Fundamental mechanisms of cardiovascular disease and repair
Molecular analyses of endothelial cells (ECs) and blood from patients with pulmonary arterial hypertension (PAH) are being used to identify novel biomarker and therapeutic targets for this lethal disease, for example our recent discovery that TPT-1 (TCTP) mediates growth-dysregulation of ECs in complex arterial remodeling (Circulation 2014). Analyses at the proteome level, mRNA and miRNA, will lead to further dissection of the molecular underpinnings of this disease, for example, our identification of circulating miR-26a as a biomarker for PAH (AJRCCM 2013). Multi-tiered profiling will be used to study stem cell differentiation and dysfunction, informing new approaches for “enhanced” cell therapy for cardiovascular diseases.

Innovative approaches to address critical limitations to effective cell therapies
The Stewart Lab is focusing on overcoming major limitations of current cell therapies, beyond the use of gene-enhancement strategies to “rejuvenate” autologous progenitor cells, which we have now applied in two clinical trials. Our goal is to overcome the effect of age and co-morbidities on the activity of a patient’s own stem cells, using strategies to overcome cell senescence and/or dysfunction. Lack of cell persistence often precludes stem cells acting directly to regenerate damaged tissue by transdifferentiation. A novel “cocooning” technology pioneered in our lab uses a combinatorial cell-matrix approach to envelope single stem cells with functionalized hydrogel “cocoons”, increasing cell survival and engraftment. This is being transferred to an “on chip” microfluidic platform suitable for scale up to support large-scale preclinical and, ultimately, clinical testing.

Impactful human trials of innovative regenerative therapies
We are also spearheading the translation of the most promising approaches into innovative, first-in-human clinical trials and propose to translate the innovative new technologies developed above into the “next generation” of cell therapy trials. We have launched the first enhanced progenitor cell therapy trial for post heart attack repair and been guiding the Cellular Immunotherapy for Septic Shock (CISS) trial from our initial discovery to a phase 1 study. In the near future, PHACeT-2 will utilize strategies to yield more efficient and durable cell transfection. Future cardiac and pulmonary trials will use novel cell products developed above; i.e., exosomes or combinatorial cell products reproducing a portable stem cell niche.