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· Molecular and cellular biology
· Disease modeling
Neural crest cells (NCCs) are highly migratory stem cells, which give rise to the entire peripheral nervous system (PNS), smooth muscle of major blood vessels, cartilage and bone of the face, endocrine cells in the thyroid and adrenal glands and melanocytes of the skin. Hence, defects in NC development in human yield a large array of diseases, accounting for most of the human congenital disorders.
Our group focuses mainly on NC and PNS development, particularly on two common NC associated diseases: Hirschsprung's disease (HSCR; colonic aganglionosis) and neuroblastoma (NB). HSCR is attributed to a failure of enteric NCC to fully colonize the gut, leading to absence of ganglion in the bowel, while NB is the most common childhood solid tumor derived from improperly differentiated NCCs in adrenal glands and sympathetic nervous system.
Enteric nervous system
We have integrated genetics, statistics and bioinformatics with experimental biology to investigate the genetic and molecular mechanisms underlying ENS and HSCR development.
Molecular basis of the enteric nervous system development and Hirschsprung's disease
Enteric nervous system (ENS) in mammals is derived from the enteric NCCs. These precursor cells extensively proliferate to expand, migrate over a long distance to fully colonize the developing gut, and differentiate into millions of neuron and glia which are organized into the network to coordinate the complex behaviors of the gut. Failure of the enteric NCCs to form ganglia in the hindgut may result in HSCR.
We are the first group to demonstrate that Hedgehog (Hh) signaling is implicated in both the maintenance of ENS progenitors and its subsequent lineage commitment, and that abnormal glial differentiation is a novel disease mechanism for HSCR (Ngan et al J Clin Invest. 2011). An important next step is to understand how these Hh signaling molecules regulate the lineage determination of ENCCs and contribute to HSCR susceptibility. By making use of the established single and compound mouse mutants that carry mutations in various Hh signaling components including Sufu, Sox10, Gli2, Gli3, and a new mouse line carrying Gli-reporter, we aim to further decipher the molecular and cellular events underlying this process.
Use patient specific iPSC for studying human NC development and disease etiology for HSCR
Early stages of human gestation are virtually inaccessible for experimental research, making human induced pluriopotent stem cell (iPSC) culture a unique model for studying the development of human NC lineages and the associated diseases. To date, with defined differentiation conditions, iPSC can be dictated to form neural rosettes that comprise cells expressing early neuroectodermal markers. Importantly, in response to appropriate developmental patterning cues, these neuroepithium-like cells are capable of progressing toward different NC lineages and differentiating into varied region-specific neural and non-neural NC derivatives. Currently, we have established a catologue of patient specific iPSC lines and an appriopiate NC models for HSCR disease. By integrating the next-generation sequencing data on the patients, we aim to identify not only the causative genes, but also the molecular pathways implicated in disease pathogenesis.
Implication of neuroblastoma tumor initiating cell in determining tumor behavior
Under the framework of cancer stem cell (CSC) or tumor initiating cell (TIC) hypothesis, cancer cells are hierarchically organized in a tumor bulk. TICs give rise to phenotypically heterogeneous progenies, contributing to the wide range of clinical presentations and non-uniform response to the treatment of NB. Fibromuscular and glial lineage commitment of TIC favors tumor regression and maturation, respectively, whereas differentiation to the neuronal lineage results in a malignant tumor progression. In my laboratory, different NB-TIC lines derived from primary and bone-marrow metastasized tumors have been establised and used to generate in vivo models for understanding NB initiation, growth and progression.