Chemical Approaches to Stem Cell Biology and Regeneration

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Areas of investigation
We are interested in developing and applying innovative chemical approaches to stem cell biology and regeneration, with a focus on discovering and characterizing novel small molecules that can control cell fate and function of various cell types, including stem cell maintenance, activation, differentiation and reprogramming in various developmental stages and tissues.

Significance
Recent advances in stem cell biology may make possible new approaches for the treatment of a number of diseases including cardiovascular disease, neurodegenerative disease, musculoskeletal disease, diabetes and cancer.

These approaches could involve cell replacement therapy and/or drug treatment to stimulate the body's own regenerative capabilities by promoting survival, migration/homing, proliferation, differentiation and reprogramming of endogenous stem/progenitor cells or more differentiated cells. However, such approaches will require identification of renewable sources of functional cells, an improved ability to manipulate their fate and function, as well as a better understanding of the mechanisms that control their fate/function. Our studies are designed to address the above challenges, and will ultimately facilitate the therapeutic application of stem cells and the development of small molecule drugs to stimulate tissue and organ regeneration in vivo.

Approaches
Equipped with high throughput screening platform and large arrayed chemical libraries, we have been constantly developing and integrating new chemical and functional genomic tools to study stem cell biology and regeneration. Our current works have focused on screening the chemical libraries to identify and further characterize small molecules that can control stem cell fate in various systems. Moreover, major efforts are devoted to characterize the molecular mechanism of these identified small molecules using various approaches, including detailed structure-activity-relationship (SAR) studies, affinity chromatography for target identification, transcriptome profiling, proteomics analysis, chemical/genetic epistasis, and biochemical and functional assays in vitro and in vivo. So far, functional small molecules and fundamental mechanisms have been identified and are being characterized in each of the above twenty plus distinct biological processes involving regulation of stem/progenitor cells. More recent examples include identification and characterization of distinct small molecules for hESC self-renewal and clonal expansion/survival; dopaminergic neuron specification from ESCs; derivation of naïve pluripotent stem cells from various species; reprogramming of somatic cells to pluripotent (e.g., iPS cells) or lineage-specific (e.g., transdifferentiation) stages under chemically defined conditions; chemically defined conditions for self-renewal of adult stem cells; directed differentiation to neural, endoderm, and cardiac lineages; and proliferation of human beta cells.

Contributions

  1. Developed the first protein-transduction technology for iPSC reprogramming and generated the first protein-induced pluripotent stem (piPS) cells from somatic cells without using any genetic materials and genetic manipulation (Cell Stem Cell, 4, 381-384, 2009). This method and such piPS cells provide safer cells for personalized regenerative medicine and more effective platform for human disease modeling.
  2. First discovered a series of small molecules and conditions that can replace reprogramming transcription factors and enhance reprogramming efficiency in generating iPS cells from somatic cells (Cell Stem Cell, 2008/2009/2010, Nature Method, 2009).
  3. Develop a novel reprogramming paradigm for generating heart, brain, and pancreatic cells directly from skin fibroblasts (Nature Cell Biology and PNAS, 2011).
  4. First developed a method and generated a novel type of human pluripotent stem cells that represents an earlier pluripotency (naïve) stage and a true equivalent of classic murine ESCs (Cell Stem Cell 4, 16-19, 2009). These novel human pluripotent stem cells may serve as better materials for regenerative medicine.
  5. First identified a number of different synthetic small molecules that can control various cell fate, including stem cell self-renewal, differentiation, and lineage-specific reprogramming, and developmental and disease pathways (series papers in JACS, 2004, and PNAS, 2006/2007).

Some questions addressed in ongoing studies:
Our current works have focused on screening the chemical libraries to identify and further characterize small molecules that can control stem cell fate in various systems, including:

  1. Self-renewal regulation of embryonic and adult stem cells
  2. Directed and step-wised differentiation of embryonic stem cells toward neuronal, cardiac and pancreatic lineages
  3. Subtype specification of human tissue-specific stem/progenitor cells
  4. Cellular plasticity and reprogramming of lineage-restricted somatic cells to alternative cell fate (e.g., toward iPSCs or transdifferentiation)
  5. Functional proliferation of adult cardiomyocytes and pancreatic beta cells
  6. Developmental signaling pathways (i.e. Wnt, Hh, BMP and FGF) and epigenetic mechanisms (histone and DNA de/methylation)
  7. Development of new technologies for drug discovery.