Publications

Background: Mural cells synthesize and deposit laminin to the basement membrane. To investigate the function of mural cell-derived laminin, we generated a mutant mouse line lacking mural cell-derived laminin (termed PKO). In a previous study, we showed that the PKO mice were grossly normal under homeostatic condition, but developed blood-brain barrier (BBB) breakdown with advanced age (> 8 months), suggesting that these mutants are intrinsically weak. Based on these findings, we hypothesized that PKO mice have exacerbated injuries in pathological conditions.

Methods: Using collagenase-induced intracerebral hemorrhage (ICH) as an injury model, we examined various stroke outcomes, including hematoma volume, neurological function, neuronal death, BBB integrity, paracellular/transcellular transport, inflammatory cell infiltration, and brain water content, in PKO mice and their wildtype littermates at young age (6-8 weeks). In addition, transmission electron microscopy (TEM) analysis and an in vitro ICH model were used to investigate the underlying molecular mechanisms.

Results: Compared to age-matched wildtype littermates, PKO mice display aggravated stroke outcomes, including larger hematoma size, worse neurological function, increased neuronal cell death, enhanced BBB permeability, increased transcytosis, and elevated inflammatory cell infiltration. These mutants also exhibit high baseline brain water content independent of aquaporin-4 (AQP4). In addition, mural cell-derived laminin significantly reduced caveolin-1 without affecting tight junction proteins in the in vitro ICH model.

Conclusions: These results suggest that mural cell-derived laminin attenuates BBB damage in ICH via decreasing caveolin-1 and thus transcytosis, regulates brain water homeostasis, and plays a beneficial role in ICH.

Brain pericytes synthesize and deposit laminin at the blood-brain barrier (BBB). The function of pericyte-derived laminin in BBB maintenance remains largely unknown. In a previous study, we generated pericytic laminin conditional knockout (PKO) mice, which developed BBB breakdown and hydrocephalus in a mixed genetic background. However, since hydrocephalus itself can compromise BBB integrity, it remains unclear whether BBB disruption in these mutants is due to loss of pericytic laminin or secondary to hydrocephalus. Here, we report that, in C57Bl6 dominant background, the PKO mice fail to show hydrocephalus, have a normal lifespan, and develop BBB breakdown in an age-dependent manner. Further mechanistic studies demonstrate that abnormal paracellular transport, enhanced transcytosis, decreased pericyte coverage, and diminished AQP4 level are responsible for BBB disruption in PKO mice. These results suggest that pericyte-derived laminin plays an indispensable and age-dependent role in the maintenance of BBB integrity under homeostatic conditions.

Intracerebral hemorrhage (ICH) is a cerebrovascular disorder with high mortality and disability rates. Although a lot of effort has been put in ICH, there is still no effective treatment for this devastating disease. Recent studies suggest that oligodendrocytes play an important role in brain repair after ICH and thus may be targeted for the therapies of ICH. Here in this review, we first introduce the origin, migration, proliferation, differentiation, and myelination of oligodendrocytes under physiological condition. Second, recent findings on how ICH affects oligodendrocyte biology and function are reviewed. Third, potential crosstalk between oligodendrocytes and other cells in the brain is also summarized. Last, we discuss the therapeutic potential of oligodendrocyte‐based treatments in ICH. Our goal is to provide a comprehensive review on the biology and function of oligodendrocytes under both physiological and ICH conditions.

At the blood-brain barrier (BBB), laminin-α5 is predominantly synthesized by endothelial cells and mural cells. Endothelial laminin-α5 is dispensable for BBB maintenance under homeostatic conditions but inhibits inflammatory cell extravasation in pathological conditions. Whether mural cell-derived laminin-α5 is involved in vascular integrity regulation, however, remains unknown. To answer this question, we generated transgenic mice with laminin-α5 deficiency in mural cells (α5-PKO). Under homeostatic conditions, no defects in BBB integrity and cerebral blood flow (CBF) were observed in α5-PKO mice, suggesting that mural cell-derived laminin-α5 is dispensable for BBB maintenance and CBF regulation under homeostatic conditions. After ischemia-reperfusion (MCAO) injury, however, α5-PKO mice displayed less severe neuronal injury, including reduced infarct volume, decreased neuronal death, and improved neurological function. In addition, α5-PKO mice also showed attenuated vascular damage (milder BBB disruption, reduced inflammatory cell infiltration, decreased brain edema, and diminished hemorrhagic transformation). Mechanistic studies revealed less severe tight junction protein (TJP) loss and pericyte coverage reduction in α5-PKO mice after ischemia-reperfusion injury, indicating that the attenuated ischemic injury in α5-PKO mice is possibly due to less severe vascular damage. These findings suggest that mural cell-derived laminin-α5 plays a detrimental role in ischemic stroke and that inhibiting its signaling may have a neuroprotective effect.

Endothelial cells make laminin-411 and laminin-511. Although laminin-411 is well studied, the role of laminin-511 remains largely unknown due to the embryonic lethality of lama5^−/− mutants. In this study, we generated endothelium-specific lama5 conditional knockout (α5-TKO) mice and investigated the biological functions of endothelial lama5 in blood brain barrier (BBB) maintenance under homeostatic conditions and the pathogenesis of intracerebral hemorrhage (ICH). First, the BBB integrity of α5-TKO mice was measured under homeostatic conditions. Next, ICH was induced in α5-TKO mice and their littermate controls using the collagenase model. Various parameters, including injury volume, neuronal death, neurological score, brain edema, BBB integrity, inflammatory cell infiltration and gliosis, were examined at various time points after injury. Under homeostatic conditions, comparable levels of IgG or exogenous tracers were detected in α5-TKO and control mice. Additionally, no differences in tight junction expression, pericyte coverage and astrocyte polarity were found in these mice. After ICH, α5-TKO mice displayed enlarged injury volume, increased neuronal death, elevated BBB permeability, exacerbated infiltration of inflammatory cells (leukocytes, neutrophils, and mononuclear cells), aggravated gliosis, unchanged brain edema, and worse neurological function, compared to the controls. These findings suggest that endothelial lama5 is dispensable for BBB maintenance under homeostatic conditions but plays a beneficial role in ICH.

Located at the interface of the circulation system and the CNS, the basement membrane (BM) is well positioned to regulate blood–brain barrier (BBB) integrity. Given the important roles of BBB in the development and progression of various neurological disorders, the BM has been hypothesized to contribute to the pathogenesis of these diseases. After stroke, a cerebrovascular disease caused by rupture (hemorrhagic) or occlusion (ischemic) of cerebral blood vessels, the BM undergoes constant remodeling to modulate disease progression. Although an association between BM dissolution and stroke is observed, how each individual BM component changes after stroke and how these components contribute to stroke pathogenesis are mostly unclear. In this review, I first briefly introduce the composition of the BM in the brain. Next, the functions of the BM and its major components in BBB maintenance under homeostatic conditions are summarized. Furthermore, the roles of the BM and its major components in the pathogenesis of hemorrhagic and ischemic stroke are discussed. Last, unsolved questions and potential future directions are described. This review aims to provide a comprehensive reference for future studies, stimulate the formation of new ideas, and promote the generation of new genetic tools in the field of BM/stroke research.

Laminin, an extracellular matrix protein, is widely expressed in the central nervous system (CNS). By interacting with integrin and non-integrin receptors, laminin exerts a large variety of important functions in the CNS in both physiological and pathological conditions. Due to the existence of many laminin isoforms and their differential expression in various cell types in the CNS, the exact functions of each individual laminin molecule in CNS development and homeostasis remain largely unclear. In this review, we first briefly introduce the structure and biochemistry of laminins and their receptors. Next, the dynamic expression of laminins and their receptors in the CNS during both development and in adulthood is summarized in a cell-type-specific manner, which allows appreciation of their functional redundancy/compensation. Furthermore, we discuss the biological functions of laminins and their receptors in CNS development, blood-brain barrier (BBB) maintenance, neurodegeneration, stroke, and neuroinflammation. Last, key challenges and potential future research directions are summarized and discussed. Our goals are to provide a synthetic review to stimulate future studies and promote the formation of new ideas/hypotheses and new lines of research in this field.

The blood–brain barrier (BBB) is a highly complex and dynamic structure, mainly composed of brain microvascular endothelial cells, pericytes, astrocytes and the basement membrane (BM). The vast majority of BBB research focuses on its cellular constituents. Its non-cellular component, the BM, on the other hand, is largely understudied due to its intrinsic complexity and the lack of research tools. In this review, we focus on the role of the BM in BBB integrity. We first briefly introduce the biochemical composition and structure of the BM. Next, the biological functions of major components of the BM in BBB formation and maintenance are discussed. Our goal is to provide a concise overview on how the BM contributes to BBB integrity.

Stroke is a cerebrovascular disorder that affects many people worldwide. In addition to the well-established functions of astrocytes and microglia in stroke pathogenesis, pericytes also play an important role in stroke progression and recovery. As perivascular multi-potent cells and an important component of the blood–brain barrier (BBB), pericytes have been shown to exert a large variety of functions, including serving as stem/progenitor cells and maintaining BBB integrity. Here in this review, we summarize the roles of pericytes in stroke pathogenesis, with a focus on their effects in cerebral blood flow, BBB integrity, angiogenesis, immune responses, scar formation and fibrosis.