Abstract
Intracerebral hemorrhage (ICH) is a particularly severe form of stroke, and reactive astrogliosis is a common response following injury to the central nervous system (CNS). Mesenchymal stem cells (MSCs) are reported to promote neurogenesis and alleviate the late side effects in injured brain regions. Gap junctions (Gjs) are abundant in the brain, where the richest connexin (Cx) is Cx43, most prominently expressed in astrocytes. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential transcription factor regulating antioxidant reactions. Here, we aimed to explore whether bone marrow MSCs (BM-MSCs) could alleviate brain injury and protect astrocytes from apoptosis, by regulating Cx43 and Nrf2. We validated the effect of BM-MSC transplantation in an ICH model in vivo and in vitro and detected changes using immunofluorescence, as well as protein and mRNA expression of glial fibrillary acidic protein (GFAP), vimentin (VIM), Cx43, Nrf2, and heme oxygenase-1 (HO-1). Our results showed that BM-MSC transplantation attenuated brain injury after ICH and upregulated VIM expression in vivo and in vitro. Additionally, Cx43 upregulation and Nrf2 nuclear translocation were observed in astrocytes cocultured with BM-MSC. Knockdown of Cx43 by siRNA restrained Nrf2 nuclear translocation. Cx43 and Nrf2 had a connection as determined by immunofluorescence and coimmunoprecipitation. We demonstrated that astrocytes undergo astroglial-mesenchymal phenotype switching and have anti-apoptotic abilities after BM-MSC transplantation, where Cx43 upregulation triggers Nrf2 nuclear translocation and promotes its phase II enzyme expression. The Cx43/Nrf2 interaction of astrocytes after BM-MSC transplantation may provide an important therapeutic target in the management of ICH.
Highlights
Intracerebral hemorrhage (ICH) is a severe form of stroke with high mortality and morbidity, and survivors usually have profound neurological deficits (Qureshi et al, 2009; Keep et al, 2012)
The results showed that neurological deficits were significantly reduced after BM-Mesenchymal stem cells (MSCs) transplantation at 7 and 14 days (p < 0.05 and p < 0.001, respectively; Figures 2E,F), when compared to the phosphate-buffered saline (PBS) group
We found that Nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression increased after ICH, but after bone marrow MSCs (BM-MSCs) transplantation, Nrf2 and HO-1 expression increased significantly compared to the PBS-ICH group (p < 0.05; Figure 2I and Supplementary Figures S1a-e)
Summary
Intracerebral hemorrhage (ICH) is a severe form of stroke with high mortality and morbidity, and survivors usually have profound neurological deficits (Qureshi et al, 2009; Keep et al, 2012). It is the second most common form of stroke, accounting for about 10–30% of cases, and the major causes of disability and death (Bedini et al, 2018). The secondary injury is characterized by hemoglobin breakdown products activating hemostatic cascades, and presence of clots is often accompanied by the activation of astrocytes, resulting in dense glial scars, which exacerbate neurological deterioration and affect long-term neuronal recovery (Aronowski and Zhao, 2011; Zhou et al, 2014; Moeendarbary et al, 2017)
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