Research

1. Macrophage function in spinal cord injury (SCI)

A new report by the Christopher and Dana Reeve Foundation states that almost 1.3 million Americans suffer from paralysis due to SCI. Even though stroke, which affects the mobility of 1.6 million Americans, is the leading cause of paralysis, SCI follows closely behind, accounting for 23 percent of all cases. Despite the huge amount of resources dedicated to research and human trials investigating SCI, there are currently no effective treatments. This stagnant progress is partially attributed to the complex pathophysiology of SCI, consisting of primary and secondary mechanisms. While primary injury is mechanical, secondary injury involves damage that occurs at the cellular levels, which corresponds to functional deficits. Moreover, the mechanisms underlying secondary injury remain largely unknown.

Macrophages play a very important role in the inflammatory responses involved with SCI. Our studies show that infiltrated bone marrow derived macrophages at the injury site engulf myelin debris to form myelin-laden macrophages. These cells then promote disease progression due to their pro-inflammatory phenotype, enhanced neurotoxicity, and impaired phagocytic capacity for apoptotic cells. As such, we proposed a new mechanism for secondary injury: the excessive accumulation of myelin-laden macrophages is the root of secondary injury and targeting these macrophages could represent an effective strategy to improve the local inflammatory microenvironment in injured spinal cords and further motor neuron function recovery.  

2. Therapeutic strategies for SCI based on the restoration of local phagocytic capacity

Since myelin-laden macrophages accumulated in the injured spinal cord lose their normal phagocytic capacity, necrotic tissues and cells, which cannot be cleared from the injured spinal cord, may exacerbate secondary damage. Hence, we have designed a series of studies to explore possible treatments and investigate whether the restoration of local macrophage phagocytic capacity can ameliorate secondary injury and promote motor neuron function recovery. We hope these studies will be beneficial to SCI recovery and can be applied to human patients.

3. Tumorigenicity of stem cells / Stem cell therapy holds enormous potential as a treatment for many diseases, including SCI. However, the risk of tumor (teratoma) development is a major obstacle to successful clinical translation of embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC). Therefore, potential tumorigenicity must be evaluated directly before clinical application of any stem cell type in regenerative medicine. We discovered that syngeneic ESC transplants into the spinal cord recruit bone marrow-derived macrophages that produce macrophage migration inhibitory factor (MIF), which stimulates angiogenesis and teratoma development. Pharmacological blockage of MIF was effective in reduceing teratoma development in spinal cords after ESC transplantation. In addition, we demonstrated that ESCs could induce macrophages to transition from tumor killing to tumor supporting cells. ESCs express special molecules that maintain macrophage tumor supporting phenotype and activate the “angiogenic switch” of macrophages to support blood vessel growth, promoting teratoma development. Our studies suggest that the induction of tumor supporting macrophages is an important mechanism for teratoma development. Thus, strategies targeting macrophages in order to inhibit teratoma development would increase the safety of ESC-based therapies.

Current Research:

1. To demonstrate the pathophysiological roles of myelin-laden macrophages in SCI and provide experimental support for novel therapeutic interventions.

2. To study the underlying biologic pathways associated with stem cell-induced macrophage activation.

3. To understand the molecular basis of autism spectrum disorders (ASD) based upon large-scale gene expression profiling and to explore whether inflammatory response, particularly macrophage activation, contributes to the pathogenesis of ASD.