Transplantation Of Induced Pluripotent Stem Cells Alleviates Cerebral Acute Inflammation And Nerve Cell Damage In Hemorrhagic Stroke

Intracerebral haemorrhage(ICH) is a stroke subtype which is associated withhigh mortality and disability and there exists no effective treatment. Mechanismsunderlying brain injury induced by intracerebral haemorrhage are very complex. Theprimary injury is mainly reflected in the hematoma formation and its expansionwithin brain parenchyma. The secondary injury is caused by three intertwineddegenerative cascades including inflammation, red cell lyses and thrombin production,which induce severe neural dysfunctions by the formation of cerebral edema,neuronal apoptosis and degeneration，even death. Accumulating evidence has shownthat cerebral inflammation plays an extremely key role in the ICH-induced secondarybrain damages, and suggested that various inflammatory pathways can be serve aspromising therapeutic targets for treating ICH.Stem cell-based approaches have already developed into effective therapies torestore function in experimental ICH. Induced pluripotent stem cells (iPSCs) are novel stem cell populations induced from adult somatic cells through reprogrammingby definite transcription factors, and regarded as promising candidates for clinical celltherapies without the problems of ethics or immunogenicity. Recent studies haveindicated that it could reduce the inflammatory damages in ischemic stroke and otheranimal models of human diseases. However, it remains unclear whether iPSCstreatment has possible anti-inflammation potential on the innate inflammatoryresponse after acute hemorrhagic stroke. In this study, we primarily plan to explore itstherapeutic effects on acute cerebral inflammation, then neural damage and recoveryin a rat collagenase-induced hemorrhagic model.Objective:We primarily plan to explore the therapeutic effects of iPSCs transplantation on acutecerebral inflammation, then neural damage and recovery in a rat collagenase-inducedhemorrhagic model.Methods:1. ICH models were established by stereotactic injection of collagenase VII into theleft striatum of male Sprague-Dawley (SD) rats. Sham ICH rats were establishedby injection of sterile saline (n=20). Six hours later, ICH rats were randomlydivided into2groups (n=30/group) and received intracerebrally5μl of PBS withor without1×106iPSCs respectively, as iPSCs group or PBS group;2. Subsequently, neural function of all ICH rats were periodically assessed at days0,1,3,7,14,28and42after ICH with MLPT. Eventually, cytokines weredetermined at48hours, inflammatory cells and neural apoptosis in ratperihematomal region, and brain water content were determined respectively atday3;3. Nissl+cells, glial fibrillary acidic protein GFAP+cells and transplanted iPSCs inrat perihematoma were detected respectively at day42.Results: 1. Compared with control animals, the iPSCs-transplanted rats showed improvedneurological function in modified limp placing test (MLPT) scores from day14to day42(P＜0.01respectively);2. IPSCs transplantation reduced infiltrations of neutrophils and microglia,apoptosis (P＜0.05respectively), brain water content (P＜0.05), and decreasedexpressions of IL-1β, IL-6and TNF-α (P＜0.01respectively), whereas increasedexpression of IL-10(P＜0.05);3. IPSCs were still in the perihematomal region of iPSC-treated rats42days postICH, and reduced injured neurons and glial scar (P＜0.05).Conclusion:iPSCs transplantation may enhance the functional recovery after ICH byattenuating cerebral acute inflammation and injuries.