Background-Endothelial progenitor cells (EPCs) are known to promote neovascularization in ischemic diseases. Recent evidence suggested that diabetic neuropathy is causally related to impaired angiogenesis and deficient growth factors. Accordingly, we investigated whether diabetic neuropathy could be reversed by local transplantation of EPCs. Methods and Results-We found that motor and sensory nerve conduction velocities, blood flow, and capillary density were reduced in sciatic nerves of streptozotocin-induced diabetic mice but recovered to normal levels after hind-limb injection of bone marrow-derived EPCs. Injected EPCs were preferentially and durably engrafted in the sciatic nerves.A portion of engrafted EPCs were uniquely localized in close proximity to vasa nervorum, and a smaller portion of these EPCs were colocalized with endothelial cells. Multiple angiogenic and neurotrophic factors were significantly increased in the EPC-injected nerves. These dual angiogenic and neurotrophic effects of EPCs were confirmed by higher proliferation of Schwann cells and endothelial cells cultured in EPC-conditioned media. Conclusions-We demonstrate for the first time that bone marrow-derived EPCs could reverse various manifestations of diabetic neuropathy. These therapeutic effects were mediated by direct augmentation of neovascularization in peripheral nerves through long-term and preferential engraftment of EPCs in nerves and particularly vasa nervorum and their paracrine effects. These findings suggest that EPC transplantation could represent an innovative therapeutic option for treating diabetic neuropathy. Key Words: angiogenesis Ⅲ diabetes mellitus Ⅲ progenitor cells Ⅲ diabetic neuropathy P eripheral neuropathy is the most common complication of diabetes mellitus, affecting up to 60% of diabetic patients. 1 Loss of sensation in the feet, the most frequent manifestation of diabetic neuropathy (DN), frequently leads to foot ulcers and may progress into amputation of the limb. 2,3 Despite a continuous increase in the incidence of diabetes mellitus and DN, current treatments have yet to effectively treat DN. Our group reported that experimental DN is characterized by reduced microcirculation in peripheral nerves caused by the destruction of the vasa nervorum and thus administration of angiogenic factors such as vascular endothelial growth factors (VEGFs), sonic hedgehog (SHh), and statin could restore neural function by augmenting angiogenesis. 4 -6 In addition, deficiency of neurotrophic factors is regarded as one of the most plausible mechanisms underlying DN. 7 Alterations of nerve growth factor, ciliary neurotrophic factor, glial-derived neurotrophic factor, and brain-derived neurotrophic factor have been reported. 8 -12 However, in clinical trials, single neurotrophic cytokines turned out to be ineffective for treating DN. 13 Recently, many classic angiogenic factors were shown to possess neurotrophic activities and vice versa. VEGF, [14][15][16]17,18 Received April 29, 2008; accepted November 28, 2008. Cli...

CD45 is a membrane tyrosine phosphatase that modulates the function of the hematopoietic cells. In vitro, agonist antibodies to CD45RO or CD45RB isoforms have been shown to suppress microglial activation, but whether microglia in vivo express these isoforms in HIV encephalitis (HIVE) is unknown. Brain sections from control and HIVE were immunostained for CD45 isoforms using exon-specific antibodies (RA, RB, RC and RO). RA and RC were limited to rare lymphocytes, while RB expression was robust in microglia and inflammatory cells. RO was low in control microglia, but increased in HIVE. RO was also localized to macrophages and CD8+ T cells. Targeting CD45 in vivo with isoform-specific antibodies remains a therapeutic option for neuroinflammatory diseases. Pathol 2006;16:256-265. Brain INTRODUCTIONThe leukocyte common antigen (LCA: CD45) is a prototype transmembrane protein tyrosine phosphatase (PTPase) and is expressed in all nucleated hematopoietic cells (54). The CD45 protein exists as multiple isoforms as a result of alternative splicing of variable exons (4/A, 5/B and 6/C); the largest isoform (ABC) includes all three of these exons and the smallest isoform (O) lacks all three exons. Five different isoforms of CD45 (ABC, AB, BC, B and O) have been identified on human leukocytes and these can be recognized by antibodies specific to variable exons (A, B or C) or by αCD45RO (45). Although the extracellular domains differ among different isoforms, all forms share identical transmembrane and cytoplasmic domains including the phosphatase domains (52, 54).CD45 is one of the most abundantly expressed molecules in lymphocytes (comprising approximately 10% of all surface proteins) and is crucial in lymphocyte development and antigen signaling (2,12,23,54). Consequently, CD45 mutations are associated with severe combined immunodeficiency in mice and humans (5,28,51). In lymphocytes, CD45 is expressed in a cell subset-specific and activation-dependent manner. For instance, naïve T cells express a high molecular weight isoform (RA+/RO−) but upon activation switch to the smallest isoform (RA−/RO+) (16,31). At the cellular level, the CD45 phosphatase targets several families of proteins, including the Src family tyrosine kinases and Janus kinases (41), resulting in positive or negative signaling (2,4,54). In addition to lymphocytes, recent studies demonstrate that CD45 can modulate activation and proliferation of several inflammatory cell types including granulocytes, mast cells and monocytelineage cells, broadening its role as a regulator of inflammatory responses (8,20,35,48,57).In the central nervous system (CNS), microglia constitute a distinct glial cell population that is derived from hematopoietic cells in the bone marrow (17, 29, 42). As resident brain macrophages, microglia function as sentries, but when activated they can mediate tissue damage, a scenario considered for several CNS inflammatory disorders (10,15,27). In AIDS dementia and HIV encephalitis (HIVE), microglia and macrophages are productively infected by ...