EFFECTS OF HYALURONAN ON NEURAL STEM CELL HOMING AND DIFFERENTIATION

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 将成体神经干细胞（aNSC）全身注射到患有实验性自身免疫性脑脊髓炎（EAE）的小鼠中可以提供新的少突胶质细胞来源，该少突胶质细胞可以对脱髓鞘或髓鞘障碍的轴突进行髓鞘再生。然而，全身注射的aNSCs通常无法分化，并且在脱髓鞘病变的血管周围区域保持未分化状态，它们促进血源性CNS浸润性脑炎T细胞的凋亡。我们发现高分子量形式的透明质酸 (HA) 在脱髓鞘病变中积聚并抑制少突胶质细胞祖细胞的成熟。 HA的主要受体是CD44跨膜糖蛋白。我们的初步数据表明，HA 和 CD44 调节与 aNSC 在脱髓鞘病变中的行为相关的功能，包括 NSC 分化和促炎细胞因子的产生。我们认为CD44和HA是aNSC募集到脱髓鞘病变的关键介质，并且HA至少可以调节NSC是否分化为髓鞘细胞或无法分化并促进HA聚集的血管周围区域的T细胞凋亡。在本研究中，我们旨在检验以下假设：（1）高分子量HA抑制aNSC分化； (2) NSC 归巢至 EAE 病变取决于 CD44 和 HA 之间的相互作用； (3) HA 调节 NSC 的免疫调节活性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Systemic injection of adult neural stem cells (aNSCs) into mice with experimental autoimmune encephalomyelitis (EAE) can provide a source of new oligodendrocytes that can remyelinate demyelinated or dysmyelinated axons. However, systemically-injected aNSCs often fail to differentiate and remain undifferentiated in peri-vascular domains of demyelinated lesions where they promote apoptosis of blood-born CNS-infiltrating encephalitogenic T cells. We discovered that a high molecular weight form of hyaluronan (HA), accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor cell maturation. The major receptor for HA is the CD44 transmembrane glycoprotein. Our preliminary data suggest that HA and CD44 regulate functions relevant to how aNSCs behave in demyelinated lesions, including NSC differentiation and production of pro-inflammatory cytokines. We propose that CD44 and HA are critical mediators of aNSC recruitment to demyelinated lesions and that HA, at least, can regulate whether NSCs differentiate into myelinating cells or fail to differentiate and promote T cell apoptosis at perivascular domains where HA accumulates. In this study, we aim to test the hypotheses: (1) That high molecular weight HA inhibits aNSC differentiation; (2) That NSC homing to EAE lesions depends on interactions between CD44 and HA; and (3) That HA regulates the immunomodulatory activities of NSC.