Laminin is a trimeric protein with many isoforms. Interestingly, different cell types synthesize distinct laminin isoforms. We have found that astrocyte-derived laminin actively maintains BBB integrity via regulating mural cell differentiation; endothelial laminin regulates BBB integrity mainly via transcytosis; and pericyte-derived laminin contributes to BBB integrity in an age-dependent manner. These results suggest that distinct laminin isoforms differentially regulate BBB integrity.

Based on laminin’s function in BBB maintenance, we hypothesize that laminin may affect the pathogenesis and outcomes of various neurological disorders, including stroke and Alzheimer’s disease. We have recently shown that ablation of mural cell-derived laminin-γ1 or endothelial laminin-α5 aggravates hemorrhagic brain injury, while loss of mural cell-derived laminin-α5 attenuates ischemic brain injury. These findings pave the way for developing laminin-based therapies in stroke. We are currently investigating how loss of laminin affects Alzheimer’s disease.

Laminin expression and turnover profiles in the CNS remain unknown. This is mainly due to the large number of laminin isoforms and the lack of research tools to accurately examine each cell type-derived laminin. We are developing innovative laminin reporter mouse lines, which allow investigation of laminin expression and turnover in a cell-specific and Cre-dependent manner. Using these genetic tools, we hope to generate a comprehensive expression/turnover profile for each cell type-derived laminin in the CNS. This information will shed light on an understudied yet extremely important field and open doors for new research. 

Pericytes and fibroblasts are two less studied cell populations in the CNS. Their biology and functions under physiological and pathological conditions are mostly unclear. By using novel genetic models, we are able to selectively ablate these cells. We are characterizing the phenotypes of the resulting mice with or without brain injury and exploring the underlying molecular mechanisms. These findings will uncover the functional significance of pericytes and fibroblasts in brain homeostasis and neurological disorders.