iPSC-derived cardiac fibroblast extracellular matrix for cardiac cell therapy

Abstract Cellular Logistics’ (CL) innovation in biomaterials offers a solution to the vexing problem of stem cell retention and integration in cardiovascular regenerative therapies. Despite great promise and andgt;20 years of research, regenerative medicine—including stem cell therapies—has yet to demonstrate significant durable regeneration in the heart. Regenerating damaged heart muscle is a challenging and complex feat—simply providing an adequate in-situ dose has proven difficult, with andlt;5% of transplanted therapeutic cells retained after 24 hours. Due to the contractile nature of the heart, transplanted stem cells are rapidly washed out of the tissue, lost to circulation. Several strategies have been developed as potential solutions, including transplanting cells in various biomaterials including hydrogels; however, none have proven successful in providing a sufficient in situ dose to afford durable regeneration. The product of CLI’s proposed SBIR will be the cardiac fibroblast-derived extracellular matrix (CF-ECM), an injectable acellular biomaterial platform for increasing in-situ stem cell delivery to the heart. Derived from the culture of human cardiac fibroblasts (CF), CF-ECM has a unique protein composition to which stem cells naturally attach; CF-ECM also attaches to the myocardium when injected into the heart, boosting stem cell in-situ dose. The long-term goal of this SBIR is to develop an iPS cardiac fibroblast (iCF) cell source to support advanced manufacturing and scale up of iCF-ECM. Currently, CL sources cadaver hearts to isolate primary CF lines; this model can be scaled up to support clinical manufacturing but iCFs have multiple potential advantages over primary CFs for commercial CF-ECM production because: (1) genetically defined cell source of unlimited supply; (2) one fully tested master cell bank with known growth characteristics; (3) expanded replicative capacity (up to passage 17); (4) reduced lot-to-lot variability of iCF-ECM product; (5) iPSC technology enables genetic modifications, thus allowing for future product improvements. Furthermore, the iCFs have a more “fetal like” phenotype resulting in ECM generation more similar to the fetal niche and potentially producing a superior product for regenerative purposes. CLI hypothesizes that iCF can be used to manufacture iCF-ECM over an expanded passage range and that iCF- ECM can be used to deliver cardiomyocytes to the infarcted heart. CLI has determined that CF-ECM has significant commercial opportunity: with ~6 million heart failure patients in the U.S. alone, the estimated market size for CF-ECM is expected to exceed $2.8B/year. CL’s platform has the potential to improve the therapeutic effect of cardiac stem cell therapies for HF—an important step toward developing effective measures to stem the burgeoning HF epidemic.Narrative Nearly 6 million Americans suffer from cardiovascular disease (CVD); however, despite andgt;20 years of research, there are no effective stem cell therapies for CVD. One of the main obstacles to this type of therapy is the fact that because the heart is continually contracting, not enough therapeutic cells remain in the heart to have any effect; cells also die unless they have the right conditions. Cellular Logistics is developing an injectable material that will provide a favorable environment in the heart so that significantly more therapeutic cells will be retained in damaged areas, thus increasing the likelihood of beneficial effects.