Based on these advances in understanding human cardiogenesis, we are developing new strategies for regenerative therapeutics, capitalizing on recent advances in stem cell and mRNA therapeutics, and then translating these advances into the biotechnology sector for the benefit of both adults and children with cardiovascular disease.
Keywords: Stem cell therapy, Developmental Biology, mRNA therapy, Heart Disease, Genetics, Biotechnology
Decoding Human Cardiogenesis
Using various approaches to study heart cell lineage and characterization of progenitor cell types in salamander, murine, NHP, and human stem cell models, we have generated an atlas of cell type intermediates in the developing human heart. Through cell labeling, single cell analyses, and genetic approaches in multiple model systems, we have uncovered new subsets of progenitors, including providing direct genetically based evidence for the existence of a claudin+ epicardial derived heart progenitor that actively replenishes the cardiac myocyte population in normal conditions and is markedly mobilized and expanded during injury, leading to near complete, spontaneous heart muscle regeneration (Eroglu et al). Understanding the molecular basis for these unique salamander epicardial features could lead to new approaches to driving the reprogramming of human epicardial lineages towards a cardiomyocyte fate. This work was supported by the KI Wallenberg Cardiovascular Initiative established in 2014, and a Distinguished Professorship Award from the Swedish Research Council (2016-2023).
Tissue Engineering 5D Heart Patches
Our ability to purify, clone, and obtain semi continuous lines of human multipotent islet positive heart progenitors from human ES cell lines has presented an opportunity to generate components from a single cell. We have identified a novel human ventricular progenitor pool, derived from human ES cells, that is capable of spontaneously forming an in vivo human ventricular heart patch in large animals after injury, leading to a clear improvement in global cardiac function. Our goal has been to implement this technology to clinical niches where a generated heart muscle "patch" can be utilized where advanced therapies are currently lacking. Based on recent studies in large animal model systems (Poch et al), this study has now advanced towards FTIH studies, in collaboration with AZ and SmartCella, This work is supported by an ERC advanced grant No 743225 (2016-2023)
A Novel Paradigm to Alter In vivo Gene Function
We have established a new mode of delivery, based on chemically modified mRNA, that escapes triggering innate immunity signals and allows for non-integrating, transient, and targeted expression in the intact heart and skeletal muscle; currently utilized to express VEGF in mouse models. Over the past decade, in collaboration with AZ and Moderna, we first translated these studies into patients with diabetes, documenting the transient reversal of diabetic vascular dysfunction, providing the first clinical proof (FTIH) of concept for an mRNA therapeutic in the human setting (Gan et al). The work has now progressed past Phase 2 studies in patients with heart disease, setting the stage for a diverse set of VEGF and other mRNA therapeutics (Collen et al) We have also used this mRNA technology to drive the loss of function of an intracellular membrane bound inhibitor of calcium cycling via the expression of an intrabody (intracellular single chain antibody), leading to the reversal of cardiac dysfunction (de Genst et al). This work was supported by the AZ-KI Integrated Cardiometabolic Center (ICMC) (2015-2021).