The Regenerative Medicine Research Program (RMP) centres on the use of cells and biomaterials to reconstruct cell compartments, tissues and organs affected by trauma, genetic mutations, disease or age. In essence, its aim is to replace, renew, regenerate or reconstruct tissues, organs or body parts when required, an endeavour that will require contributions from multiple fields, including stem cell biology, cell biology, biomaterials, bioengineering, immunology and medicine.
The derivation of human embryonic stem cells and induced pluripotent stem cells has created great interest due to their potential ability to differentiate into any cell type of the adult body. Pluripotent stem cells can be cultured in vitro and expanded indefinitely. By manipulating the substrate and culture conditions, the cells can be induced to abandon the pluripotent state and commit to a given germ layer. Further manipulation allows differentiation to multipotent progenitors and eventually to mature differentiated cell types. The production of large numbers of specific differentiated cell types for transplantation has now become a possibility within reach, opening the door to the development of therapies for diseases that currently have little or no treatment. At the CBMR within the RMP, we will focus on cardiovascular disease, neurodegenerative disorders, diabetes and lysosomal storage disorders. In particular, our goal is to produce cardiomyocytes for cardiac cell therapy, neuronal cell types for neurodegenerative disease, insulin producing cells for diabetes and the creation of cell models of lysososmal storage disorders that will facilitate the development of therapeutic compounds for the treatment of these serious diseases.
On the path from bench to bedside, a long list of technical challenges must be overcome in order to make regenerative medicine a clinical reality. It will be crucial to obtain a thorough understanding of the molecular basis of pluripotency and the regulatory mechanisms involved in maintaining the pluripotent state. To this end, the RMP is developing methods to culture large amounts of these cells in bioreactors while maintaining their genomic integrity and pluripotency.
In addition to the production of specific cell types, specific disease models are also being developed within the RMP to be used to investigate the underlying mechanism of disease, allowing the development of novel therapeutic compounds. This approach involves taking fibroblasts from patients with genetic disorders and reprogramming them to the pluripotent state. In a later step within the RMP, these cells are differentiated to disease relevant cell type(s) for basic mechanistic studies and as a platform to develop novel therapies. Within the RMP, this approach will be applied to both cardiovascular diseases and lisosomal storage diseases.
RMP main research lines
Control of the pluripotent regulatory state and study of neural, cardiac and pancreatic progenitors
Robust differentiation protocols will require detailed understanding of the pluripotent state, its maintenance and how to exit towards particular lineages. Importantly, this stage is the main point of expansion of the cell populations for eventual scale up of production. Of particular interest is the work developed in genes involved in temporal and spatial integration of molecular clocks with cell cycle associated exit points from pluripotency and their relation to commitment to a particular germ layer. The RMP is actively investigating the effect of different biomaterials and nanoparticles for neuronal and cardiomyocyte differentiation. Within the RMP, biosensors and microfludic chips are used to study the effect of different biomaterials and control the addition of differentiation factors in order to optimize methodologies to control the pluripotent state of ESC, improving differentiation and reprograming efficiency.
Development of Induced Pluripotent Stem Cell (iPSc) models of Gaucher’s and Fabry Diseases
The RMP is actively developing iPSc disease models for Gaucher’s (neuronopathic form) and Fabry Disease. The RMP has already developed a proof of principle iPSc based model of the neuronopathic form of Gaucher’s Disease, differentiated these cells dopaminergic neurons and tested candidate chaperone compounds using this model.
Development and characterization of pharmacological compounds for Gaucher’s Disease
The RMP is investigating chaperone compounds to treat Gaucher’s Disease. The compound-protein interactions of candidate molecules are being investigated and biophysically characterized. This includes the optimization of the pharmacokinetic profile for these compounds within the RMP.