Research

Our long-standing research interest is to investigate the molecular mechanisms underpinning glial cell development, injury, and regeneration in the healthy and diseased central nervous system (CNS) by using a combination of genetic, molecular, cellular, electrophysiological, behavioral, and high-throughput omics approaches. We use both in vitro culture systems and in vivo animal models. Our long-term goal is to devise novel therapeutic interventions for promoting myelin formation (myelination) and myelin regeneration (remyelination) in white matter injury or disorders, such as hypoxia and ischemia-induced diffuse white matter injury (periventricular leukomalacia), multiple sclerosis, Canavan disease, and others.

Figure 1 - Diagram showing basic steps of oligodendroglial myelin formation (myelination) and repair (remyelination) (Adapted from Guo et al., 2015 GLIA)

There are multiple projects ongoing in our laboratory:

Project 1: Cellular and molecular mechanisms underlying CNS myelin formation (myelination) and repair (remyelination).

Oligodendrocytes (OLs) are myelin-forming cells in the central nervous system (CNS). CNS myelin formation/repair consists of two closely-related sequential events: OL differentiation from oligodendrocyte progenitor cells and axonal (re)myelination by already differentiated OLs. Defects of these two events result in abnormalities of CNS myelin formation such as in periventricular leukomalacia and inability of myelin repair such as in multiple sclerosis. Our long term goal is to study the underlying mechanisms regulating CNS myelin formation/repair. The expression of the Wnt effector transcription factor 7-like 2 (TCF7l2, a.k.a. TCF4) in multiple sclerosis lesions is one such promising mechanism. Previous studies proposed that TCF7l2 is a negative regulator (acting through Wnt/beta-catenin signalign) of OL differentiation and CNS myelination. Recent studies including those from our own laboratory have shown that TCF7l2 positively regulates the differentiation of oligodendroglial progenitor cells (OPCs) into OLs. We are currently studying the molecular mechanisms underlying TCF7l2’s regulation of OPC differentiation and CNS myelination.

Figure 2 - Regulation of OPC differentiation and CNS myelination by TCF7l2.

Project 2: Molecular mechanisms underlying HIFa-regulated CNS angiogenesis and myelination.

CNS angiogenesis, the growth of new blood vessels from preexisting ones, starts during embryonic, persists into early postnatal development in human and rodents. Upon brain injury, such as traumatic brain injury and stroke, endogenous angiogenic attempts occur in response to increased metabolic demands. An increasing amount of animal studies demonstrate that manipulating the endogenous angiogenesis has therapeutic benefits in brain functional recovery. Investigating underlying cellular and molecular mechanisms of CNS angiogenesis during development provides new insights into therapeutic interventions of new blood vessel growth in the adult injured brain. This project aims to study the cellular and molecular mechanisms underlying HIFa-regulated CNS developmental angiogenesis.

Figure 3 - Physiological hypoxia in the early postnatal CNS. A-C, immunostaining (green) of postnatal 6 days (P6) brains that had been received hypoxyprobe pimonidazole or saline 90 min prior to tissue harvest. The hypoxyprobe binds to intracelluar components under hypoxic conditions and is visualized by immunohistochemistry using monoclonal antibody against the hypoxyprobe. D, diffused HIF1α signals (red) in the P2 spinal cord. Scale bars=20μm.

Project 3: Role of the neural stem cell factor Sox2 in CNS glial cell development and injury.

Mutations of the neural stem cell factor Sox2 are one of the major causes of human anophthalmia /microphthalmia (A/M) which not only affects eye development but also displays a variety of neurological and behavioral deficits. Sox2 is traditionally thought to only expressed in neural stem cells (NSCs) and downregulated in NSC-derived neurons and glial cells in the CNS. Our earlier study has challenged this view and demonstrated that Sox2 is highly expressed in all developing and adult astrocytes and also in reactive astrocytes in response to various injuries such as inflammatory demyelination injury of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Recently, we reported that Sox2 plays a crucial role in oligodendroglial development and regeneration (Zhang et al., 2018). We are now studying the function and the downstream pathways of Sox2 in CNS glial (oligodendroglial and astroglial) cell development and regeneration, shedding light on the neurobiological basis of developmental abnormalities in A/M patients.

Figure 4 - Sox2 is expressed by parenchymal astrocytes in adult normal and EAE spinal cord (Adapted from Guo et al., 2011 Journal of Neuroscience. (A–B) Representative images showing co-labeling of GFAP-GFP and Sox2 (arrowheads) in the spinal WM and GM of adult normal GFAP-GFP mice, respectively. (E–F) Representative images of single optical slice showing co-labeling of GFAP and Sox2 (arrowheads) in the WM and GM of D21 EAE injured spinal cord of GFAP-GFP mice, respectively.

Project 4: PARP1/PARG-mediated PARylation in CNS development and pathology.

PARP1 plays a fundamental role in DNA repair and gene expression. Excessive PARP1 hyperactivation, however, has been associated with necrotic cell death. PARP1 and/or its activity are dysregulated in the immune and central nervous system of multiple sclerosis (MS) patients and animal models. Pharmacological PARP1 inhibition was shown to be protective against immune activation and disease severity in MS animal models while genetic PARP1 deficiency studies reported discrepant results. We are using genetic tools to probe the role of glial and neuronal PARylation in CNS development and neurological disorders.

Figure 5 - Schematic drawing illustrating PARP1/PARG-mediated PARylation (Adapted from Yan et al., 2022 Advanced Science)

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