Migration of neuronal precursor cells from the external germinal layer (EGL) to the internal granular layer (IGL) is a crucial process in the development of the mammalian cerebellar cortex. These cells make up the only precursor population known to migrate away from the surface of the brain. We studied the role of the chemokine stromal-derived factor 1 (SDF-1) in the cerebellar tissue of rats and knockout mice and found (i) that it functions as an attractive guidance cue for neuronal migration and (ii) that its secretion from non-neuronal meningeal tissue is important for controlling the migration of embryonic EGL cells.SDF-1 was first noted for its role in leukocyte chemotaxis 1,2 . Notably, mice lacking SDF-1, and its receptor CXCR4, have been found to have a similar cerebellar phenotype: cerebellar granule cells appear prematurely in the internal layers of the embryo 3-5 . This suggests that SDF-1 is either directly or indirectly involved in positioning the EGL cells 3-5 . The precise role of SDF-1 in EGL migration is not yet known 6,7 -the effects of SDF-1 on embryonic EGL cells have never been tested. The migration of dissociated cells from the postnatal IGL in a Transwell assay 8 suggests that both SDF-1 and brain-derived neurotrophic factor (BDNF) are attractants for the IGL cells and that Eph-Ephrin signaling inhibits the IGL response to SDF-1. Postnatal IGL cells are derived from EGL cells that have migrated internally and differentiated, and are no longer identical to embryonic or postnatal EGL cells. Because the phenotype of SDF-1 knockout mice is determined during embryogenesis, it is important to investigate the role of SDF-1 in guiding the migration of embryonic EGL cells.We first used immunohistochemistry to examine the distribution of the SDF-1 protein in the rat cerebellum (Fig. 1). SDF-1 was present in both the embryonic and the postnatal meninges ( Fig. 1a and b). The staining with antibody against SDF-1 was done by adding exogenous SDF-1 protein (data not shown). The presence of SDF-1 in the meninges is consistent with a role for SDF-1 in guiding the migration of EGL cells. CXCR4 is expressed in the neuroepithelium, rhombic lip and EGL of the embryonic and postnatal cerebellum 3,8,9 .The phenotype of SDF-1 knockout mice may indicate an indirect role for SDF-1 in regulating the environment through which the neurons can migrate 3,4 . In the nervous system, a single molecule can be either an attractant or repellant, depending on the cell types and intracellular (Fig. 2a), but HEK cells expressing SDF-1 did (Fig. 2b). HEK cells expressing the chemokine RANTES could neither attract nor repel EGL cells (Fig. 2g), indicating that embryonic EGL cells specifically responded to SDF-1 as a chemoattractant. To rule out the possibility that there were indirect effects of SDF-1 expression in HEK cells, we tested the activity of purified proteins by embedding the protein of interest in a collagen block. Embryonic EGL cells were attracted by collagen blocks embedded with the SDF-1 protein (Fig. 2i), but not...
The treatment of diabetic wounds remains a major challenge in clinical practice, with chronic wounds characterized by multiple drug-resistant bacterial infections, angiopathy, and oxidative damage to the microenvironment. Herein, a novel in situ injectable HA@MnO 2 /FGF-2/Exos hydrogel is introduced for improving diabetic wound healing. Through a simple local injection, this hydrogel is able to form a protective barrier covering the wound, providing rapid hemostasis and long-term antibacterial protection. The MnO 2 /ε-PL nanosheet is able to catalyze the excess H 2 O 2 produced in the wound, converting it to O 2 , thus not only eliminating the harmful effects of H 2 O 2 but also providing O 2 for wound healing. Moreover, the release of M2-derived Exosomes (M2 Exos) and FGF-2 growth factor stimulates angiogenesis and epithelization, respectively. These in vivo and in vitro results demonstrate accelerated healing of diabetic wounds with the use of the HA@MnO 2 /FGF-2/ Exos hydrogel, presenting a viable strategy for chronic diabetic wound repair.
Background: Osteoblast differentiation is a vital process for fracture healing, and exosomes are nanosized membrane vesicles that can deliver therapeutic drugs easily and safely. Macrophages participate in the regulation of various biological processes in vivo, and macrophage-derived exosomes (MD-Exos) have recently been a topic of increasing research interest. However, few study has explored the link between MD-Exos and osteoblast differentiation. Herein, we sought to identify miRNAs differentially expressed between M1 and M2 macrophage-derived exosomes, and to evaluate their roles in the context of osteoblast differentiation. Results: We found that microRNA-5106 (miR-5106) was significantly overexpressed in M2 macrophage-derived exosomes (M2D-Exos), while its expression was decreased in M1 macrophage-derived exosomes (M1D-Exos), and we found that this exosomal miRNA can induce bone mesenchymal stem cell (BMSC) osteogenic differentiation via directly targeting the Salt-inducible kinase 2 and 3 (SIK2 and SIK3) genes. In addition, the local injection of both a miR-5106 agonist or M2D-Exos to fracture sites was sufficient to accelerate healing in vivo. Conclusions: Our study demonstrates that miR-5106 is highly enriched in M2D-Exos, and that it can be transferred to BMSCs wherein it targets SIK2 and SIK3 genes to promote osteoblast differentiation.
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