Publications

Pericytes are multipotent perivascular cells that play important roles in CNS injury. However, controversial findings exist on how pericytes change and whether they differentiated into microglia-like cells after ischemic stroke. This discrepancy is mainly due to the lack of pericyte-specific markers: the “pericyte” population identified in previous studies contained vascular smooth muscle cells (vSMCs) and/or fibroblasts. Therefore, it remains unclear which cell type differentiates into microglia-like cells after stroke. In this study, lineage-tracing technique was used to mark α-smooth muscle actin (SMA)^{low/undetectable} pericytes, vSMCs, and fibroblasts, and their fates were analyzed after ischemic stroke. We found that SMA^{low/undetectable} pericytes and fibroblasts but not vSMCs substantially proliferated at the subacute phase after injury, and that SMA^{low/undetectable} pericyte but not vSMCs or fibroblasts differentiated into Iba1⁺ cells after ischemic stroke. Further imaging flow cytometry analysis revealed that SMA^{low/undetectable} pericytes differentiated into both microglia and macrophages at day 7 after stroke. These results demonstrate that SMA^{low/undetectable} pericytes rather than vSMCs or fibroblasts differentiate into both microglia-like and macrophage-like cells after stroke, suggesting that these pericytes may be targeted in the treatment of ischemic stroke.

Pericytes are a heterogenous population that plays multiple important roles in both physiological and pathological conditions. Although many markers and transgenic mouse lines have been used to identify pericytes, these tools all have limitations. For example, many of them are not pericyte-specific and none of them are able to distinguish different subtypes of pericyte. Here, we summarize commonly used pericyte markers and transgenic mouse lines, compare their unique features and limitations, and discuss key points to consider when using these tools or interpreting data generated by using them. Identifying/developing pericyte-specific and subtype-specific markers/tools will fill the gap of knowledge and substantially move the field forward.

Adenylyl cyclases (ADCYs), by generating second messenger cAMP, play important roles in various cellular processes. Their expression, regulation and functions in the CNS, however, remain largely unknown. In this review, we first introduce the classification and structure of ADCYs, followed by a discussion of the regulation of mammalian ADCYs (ADCY1-10). Next, the expression and function of each mammalian ADCY isoform are summarized in a region/cell-specific manner. Furthermore, the effects of GPCR-ADCY signaling on blood–brain barrier (BBB) integrity are reviewed. Last, current challenges and future directions are discussed. We aim to provide a succinct review on ADCYs to foster new research in the future.

Oligodendrocytes are the cells that myelinate axons and provide trophic support to neurons in the CNS. Their dysfunction has been associated with a group of disorders known as demyelinating diseases, such as multiple sclerosis. Oligodendrocytes are derived from oligodendrocyte precursor cells, which differentiate into pre-myelinating oligodendrocytes and eventually mature oligodendrocytes. The development and function of oligodendrocytes are tightly regulated by a variety of molecules, including laminin, a major protein of the extracellular matrix. Accumulating evidence suggests that laminin actively regulates every aspect of oligodendrocyte biology, including survival, migration, proliferation, differentiation, and myelination. How can laminin exert such diverse functions in oligodendrocytes? It is speculated that the distinct laminin isoforms, laminin receptors, and/or key signaling molecules expressed in oligodendrocytes at different developmental stages are the reasons. Understanding molecular targets and signaling pathways unique to each aspect of oligodendrocyte biology will enable more accurate manipulation of oligodendrocyte development and function, which may have implications in the therapies of demyelinating diseases. Here in this review, we first introduce oligodendrocyte biology, followed by the expression of laminin and laminin receptors in oligodendrocytes and other CNS cells. Next, the functions of laminin in oligodendrocyte biology, including survival, migration, proliferation, differentiation, and myelination, are discussed in detail. Last, key questions and challenges in the field are discussed. By providing a comprehensive review on laminin’s roles in OL lineage cells, we hope to stimulate novel hypotheses and encourage new research in the field.

Fibroblasts are the most common cell type of connective tissues. In the central nervous system (CNS), fibroblast-like cells are mainly located in the meninges and perivascular Virchow-Robin space. The origins of these fibroblast-like cells and their functions in both CNS development and pathological conditions remain largely unknown. In this review, we first introduce the anatomic location and molecular markers of CNS fibroblast-like cells. Next, the functions of fibroblast-like cells in CNS development and neurological disorders, including stroke, CNS traumatic injuries, and other neurological diseases, are discussed. Third, current challenges and future directions in the field are summarized. We hope to provide a synthetic review that stimulates future research on CNS fibroblast-like cells.

Background: Neurodegenerative disorders are a group of age-associated diseases characterized by progressive degeneration of the structure and function of the CNS. Two key pathological features of these disorders are blood-brain barrier (BBB) breakdown and protein aggregation.

Main body: The BBB is composed of various cell types and a non-cellular component---the basal lamina (BL). Although how different cells affect the BBB is well studied, the roles of the BL in BBB maintenance and function remain largely unknown. In addition, located in the perivascular space, the BL is also speculated to regulate protein clearance via the meningeal lymphatic/glymphatic system. Recent studies from our laboratory and others have shown that the BL actively regulates BBB integrity and meningeal lymphatic/glymphatic function in both physiological and pathological conditions, suggesting that it may play an important role in the pathogenesis and/or progression of neurodegenerative disorders. In this review, we focus on changes of the BL and its major components during aging and in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). First, we introduce the vascular and lymphatic systems in the CNS. Next, we discuss the BL and its major components under homeostatic conditions, and summarize their changes during aging and in AD, PD, and ALS in both rodents and humans. The functional significance of these alterations and potential therapeutic targets are also reviewed. Finally, key challenges in the field and future directions are discussed.

Conclusions: Understanding BL changes and the functional significance of these changes in neurodegenerative disorders will fill the gap of knowledge in the field. Our goal is to provide a clear and concise review of the complex relationship between the BL and neurodegenerative disorders to stimulate new hypotheses and further research in this field.

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.