Intracerebral hemorrhage (ICH) induces a strong hematoma-related neuroinflammatory reaction and alters peripheral immune homeostasis. Recent research has found that gut microbiota plays a role in neurodegeneration and autoimmune diseases by regulating immune homeostasis and neuroinflammation. Therefore, we investigated the relationship between ICH, microbiota alteration, and immune responses after hematoma-induced acute brain injury. In our study, we used a mouse model of ICH, and 16S ribosomal RNA sequencing showed that ICH causes gut microbiota dysbiosis, which in turn affects ICH outcome through immune-mediated mechanisms. There was prominent reduced species diversity and microbiota overgrowth in the dysbiosis induced by ICH, which may reduce intestinal motility and increase gut permeability. In addition, recolonizing ICH mice with a normal health microbiota ameliorates functional deficits and neuroinflammation after ICH. Meanwhile, cell-tracking studies have demonstrated the migration of intestinal lymphocytes to the brain after ICH. In addition, therapeutic transplantation of fecal microbiota improves intestinal barrier damage. These results support the conclusion that the gut microbiome is a target of ICH-induced systemic alteration and is considered to have a substantial impact on ICH outcome.

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Ischemic stroke (IS) remains one of the major causes of death and disability due to the limited ability of central nervous system cells to regenerate and differentiate. Although several advances have been made in stroke therapies in the last decades, there are only a few approaches available to improve IS outcome. In the acute phase of IS, mechanical thrombectomy and the administration of tissue plasminogen activator have been widely used, while aspirin or clopidogrel represents the main therapy used in the subacute or chronic phase. However, in most cases, stroke patients fail to achieve satisfactory functional recovery under the treatments mentioned above. Recently, cell therapy, especially stem cell therapy, has been considered as a novel and potential therapeutic strategy to improve stroke outcome through mechanisms, including cell differentiation, cell replacement, immunomodulation, neural circuit reconstruction, and protective factor release. Different stem cell types, such as mesenchymal stem cells, marrow mononuclear cells, and neural stem cells, have also been considered for stroke therapy. In recent years, many clinical and preclinical studies on cell therapy have been carried out, and numerous results have shown that cell therapy has bright prospects in the treatment of stroke. However, some cell therapy issues are not yet fully understood, such as its optimal parameters including cell type choice, cell doses, and injection routes; therefore, a closer relationship between basic and clinical research is needed. In this review, the role of cell therapy in stroke treatment and its mechanisms was summarized, as well as the function of different stem cell types in stroke treatment and the clinical trials using stem cell therapy to cure stroke, to reveal future insights on stroke-related cell therapy, and to guide further studies.

Spontaneous intracerebral hemorrhage (ICH) accounts for 15% of all stroke cases. ICH is a devastating form of stroke associated with high morbidity, mortality, and disability. Preclinical studies have explored the mechanisms of neuronal death and gray matter damage after ICH. However, few studies have examined the development of white matter injury (WMI) following ICH. Research on WMI indicates that its pathophysiological presentation involves axonal damage, demyelination, and mature oligodendrocyte loss. However, the detailed relationship and mechanism between WMI and ICH remain unclear. Studies of other acute brain insults have indicated that WMI is strongly correlated with cognitive deficits, neurological deficits, and depression. The degree of WMI determines the short- and long-term prognosis of patients with ICH. This review demonstrates the structure and functions of the white matter in the healthy brain and discusses the pathophysiological mechanism of WMI following ICH. Our review reveals that the development of WMI after ICH is complex; therefore, comprehensive treatment is essential. Understanding the relationship between WMI and other brain cells may reveal therapeutic targets for the treatment of ICH.

Background White matter injury (WMI) is a major neuropathological event associated with intracerebral hemorrhage (ICH). P2X purinoreceptor 4 (P2X4R) is a member of the P2X purine receptor family, which plays a crucial role in regulating WMI and neuroinflammation in central nervous system (CNS) diseases. Our study investigated the role of P2X4R in the WMI and the inflammatory response in mice, as well as the possible mechanism of action after ICH. Methods ICH was induced in mice via collagenase injection. Mice were treated with 5-BDBD and ANA-12 to inhibit P2X4R and tropomyosin-related kinase receptor B (TrkB), respectively. Immunostaining and quantitative polymerase chain reaction (qPCR) were performed to detect microglial phenotypes after the inhibition of P2X4R. Western blots (WB) and immunostaining were used to examine WMI and the underlying molecular mechanisms. Cylinder, corner turn, wire hanging, and forelimb placement tests were conducted to evaluate neurobehavioral function. Results After ICH, the protein levels of P2X4R were upregulated, especially on day 7 after ICH, and were mainly located in the microglia. The inhibition of P2X4R via 5-BDBD promoted neurofunctional recovery after ICH as well as the transformation of the pro-inflammatory microglia induced by ICH into an anti-inflammatory phenotype, and attenuated ICH-induced WMI. Furthermore, we found that TrkB blockage can reverse the protective effects of WMI as well as neuroprotection after 5-BDBD treatment. This result indicates that P2X4R plays a crucial role in regulating WMI and neuroinflammation and that P2X4R inhibition may benefit patients with ICH. Conclusions Our results demonstrated that P2X4R contributes to WMI by polarizing microglia into a pro-inflammatory phenotype after ICH. Furthermore, the inhibition of P2X4R promoted pro-inflammatory microglia polarization into an anti-inflammatory phenotype, enhanced brain-derived neurotrophic factor (BDNF) production, and through the BDNF/TrkB pathway, attenuated WMI and improved neurological function. Therefore, the regulation of P2X4R activation may be beneficial for the reducing of ICH-induced brain injury.