Project Highlight
(1) Epigenetic regulation of adult stem cells and their role in organism aging
The life-long persistence of stem cells in the body makes them particularly susceptible to the accumulation of cellular damage. Indeed, stem cells in many tissues have been found to undergo profound changes with age, exhibiting blunted responsiveness to tissue injury, dysregulation of proliferative activities and declining functional capacities. These changes lead to reduced effectiveness of cell replacement and tissue regeneration in aged organisms. Recently, our group has identified several histone modifiers that play critical roles in controlling adult stem cell aging. Epigenetic regulation of adult stem cells, such as MSCs and NSCs, is a focused research area in our team. Such knowledge will be essential to inform development of therapeutic interventions that can slow, and perhaps reverse, age-related degenerative changes to enhance repair processes and maintain healthy function in aging tissues. In addition, since histone modifying enzymes are modifiable, development of small molecules targeting the histone modifying enzymes that are amenable to prevent replicative senescence would dramatically improve the therapeutic efficacy of stem cells.
(2) Stem cell therapy in neurological diseases
While MSC-based therapy has shown emerging benefits in treating various neurological diseases, the ultimate application of MSCs is still challenging. Our team has developed a rapid and efficient method to generate unlimited number of human neural crest stem cell-derived MSCs, which possess the properties of both NSCs and MSCs. Our recent studies have revealed that hNCSC-MSCs exhibit distinctive molecular signatures and remarkably improved neuroprotective and neuroregenerative effects on brain functional repair after injury. Along this line of research, we will use a synergistic approach to develop novel stem cell therapy for neurological diseases, integrating ideal stem cell source, better preconditioning strategy and functional biomaterials for clinical applications.
(3) Modeling pediatric cancer using human embryonic stem cells
Several highly aggressive human cancers, including malignant melanoma, neuroblastoma and Ewing’s sarcoma family tumors (ESFT) are believed to be of neural crest (NC) origin. It is recognized that the pathogenesis of these NC-derived tumors involves genetic mutations that disrupt embedded NC developmental programs. One unique approach in our team is to study the cellular and molecular origin of pediatric cancers by using hESCs as an innovative model system. Take neuroblastoma as an example, we generated human neural crest stem cells from hESCs and activated oncogene MycN at the different stage of NC development. By using this species- and development stage- appropriate platform, we have revealed that MycN disrupts NC differentiation and initiates the transformation of neural crest stem cells into neuroblastoma-initiating cells. More importantly, we have identified a group of novel genes that potentially play critical roles in the initiation of neuroblastoma. By creating hESC-based models to study the origin and biology of pediatric cancer, we aim to gain novel insights into the origin and biology of these tumors that will aid in the development of more effective, less toxic therapies.
(4) Wnt signaling pathway in oligodendrogenesis of the normal and pathological central nervous system
Oligodendrocytes play significant role in providing support and insulation to axons via myelination in the central nervous system (CNS). They are derived from oligodendrocyte progenitor cells (OPC), which persist from embryo to postnatal brain. The malfunction of oligodendrogenesis or myelin loss result in neurological disorders, such as multiple sclerosis, leukodystrophies, etc. However, the molecular mechanisms underlying oligodendrogenesis and myelination in CNS development and diseases are still elusive. The R-spondin (RSPO) family of four proteins represents a new group of secreted factors that enhance β-catenin signaling. Like WNTs, RSPOs have important roles in development and act as powerful stem cell growth factors. In this line of research, we aim to investigate the role of RSPOs in oligodendrogenesis and related diseases. These studies will not only reveal previously undefined role of RSPOs in oligodendrogenesis and brain development, but also provide important insights into the underlying mechanisms and potential therapeutic targets of demyelinating diseases.