Pharmacological Reprogramming of Somatic Cells for Regenerative Medicine.

Lost or damaged cells in tissues and organs can be replaced by transplanting therapeutically competent cells. This approach requires methods that effectively manipulate cellular identities and properties to generate sufficient numbers of desired cell types for transplantation. These cells can be generated by reprogramming readily available somatic cells, such as fibroblasts, into induced pluripotent stem cells (iPSCs), which can replicate indefinitely and give rise to any somatic cell type. This reprogramming can be achieved with genetic methods, such as forced expression of pluripotency-inducing transcription factors (TFs), which can be further improved, or even avoided, with pharmacological agents. We screened chemical libraries for such agents and identified small molecules that enhance TF-mediated pluripotency induction in somatic cells. We also developed cocktails of small molecules that can functionally replace combinations of TFs required to induce pluripotency in mouse and human somatic cells. Importantly, we devised and established a general strategy to develop effective pharmacological cocktails for specific cellular reprogramming processes. In the search for useful small molecules, we also discovered and characterized previously unknown mechanisms pertinent to cellular reprogramming. A more direct method to access scarce cells for cell transplantation is transdifferentiation, which uses combinations of cell-type specific TFs to reprogram fibroblasts into the target somatic cell types across lineage boundaries. We created an alternative strategy for cellular transdifferentiation that epigenetically activates somatic cells by pairing temporal treatment with reprogramming molecules and tissue-specific signaling molecules to generate cells of multiple lineages. Using this cell-activation and signaling-directed (CASD) transdifferentiation paradigm, we converted fibroblasts into a variety of somatic cells found in major organs, such as the heart, brain, pancreas, and liver. Specifically, we induced, isolated, and expanded (long-term) lineage-specific progenitor cells that can give rise to a defined range of cell types relevant to specific tissues or organs. Transplanting these progenitor cells or their progeny was therapeutically beneficial in animal models of diseases and organ damage. Importantly, we developed chemically defined conditions, without any genetic factors, that convert fibroblasts into cells of the cardiac and neural lineages, further extending the realm of pharmacological reprogramming of cells. Continuously advancing technologies in pharmacological reprogramming of cells may benefit and advance regenerative medicine. The established pharmacological tools have already been applied to enhance the processes of cellular reprogramming and improve the quality of cells for their clinical applications. The rapidly increasing number of readily available bioactive chemical tools will fuel our efforts to reprogram cells for transplantation therapies.