Rhynchophylline promotes stem cell autonomous metabolic homeostasis.

Rhynchophylline (Rhy) effectively obstructs the expansive signaling pathways of degenerative diseases, including Alzheimer disease, Parkinson disease, epilepsy and amyotrophic lateral sclerosis, and stimulates neurogenesis. Maintenance of stemness and cell proliferation requires sophisticated intracellular environments to achieve pluripotency via specific expression of genes and proteins. We examined whether Rhy promotes this regulation in bone marrow human mesenchymal stromal cells (BM-hMSCs). Results revealed (i) Rhy modulated biological activity by regulating the mitochondria, N-methyl-D-aspartate receptor subunit, and levels of FGFß (basic fibroblast growth factor), BDNF (brain-derived neurotrophic factor), OXTR (oxytocin receptor) and ATP (Adenosine triphosphate); (ii) Rhy altered expression level of BM-MSC proliferation/differentiation-related transcription genes; and (iii) interestingly, Rhy amplified the glycolytic flow ratio and lactate dehydrogenase activity while reducing pyruvate dehydrogenase activity, indicating a BM-hMSC metabolic shift of mitochondrial oxidative phosphorylation into aerobic glycolysis. Altogether, we demonstrated a novel mechanism of action for Rhy-induced BM-hMSC modification, which can enhance the cell transplantation approach by amplifying the metabolic activity of stem cells.

A Novel Partial MHC Class II Construct, DRmQ, Inhibits Central and Peripheral Inflammatory Responses to Promote Neuroprotection in Experimental Stroke.

Recognizing that the pathologic progression of stroke is closely associated with aberrant immune responses, in particular the activation of peripheral leukocytes, namely T cells, we hypothesized that finding a treatment designed to inhibit neuroantigen-specific T cells and block cytotoxic monocytes and macrophages may render therapeutic effects in stroke. We previously reported that subcutaneous administration of partial MHC class II constructs promote behavioral and histological effects in stroke mice by centrally promoting a protective M2 macrophage/microglia phenotype in the CNS and peripherally reversing stroke-associated splenic atrophy. Here, we employed a second species using adult Sprague-Dawley rats exposed to the middle cerebral artery occlusion stroke model and observed similar therapeutic effects with a mouse partial MHC class II construct called DRmQ, as evidenced by reductions in stroke-induced motor deficits, infarcts, and peri-infarct cell loss and neuroinflammation. More importantly, we offered further evidence of peripheral sequestration of inflammation at the level of the spleen, which was characterized by attenuation of stroke-induced spleen weight reduction and TNF-ɑ and IL-6 upregulation. Collectively, these results satisfy the Stroke Therapy Academic Industry Roundtable criteria of testing a novel therapeutic in a second species and support the use of partial MHC class II constructs as a stroke therapeutic designed to sequester both central and peripheral inflammation responses in an effort to retard, or even halt, the neuroinflammation that exacerbates the secondary cell death in stroke.

Translating intracarotid artery transplantation of bone marrow-derived NCS-01 cells for ischemic stroke: Behavioral and histological readouts and mechanistic insights into stem cell therapy.

The present study used in vitro and in vivo stroke models to demonstrate the safety, efficacy, and mechanism of action of adult human bone marrow-derived NCS-01 cells. Coculture with NCS-01 cells protected primary rat cortical cells or human neural progenitor cells from oxygen glucose deprivation. Adult rats that were subjected to middle cerebral artery occlusion, transiently or permanently, and subsequently received intracarotid artery or intravenous transplants of NCS-01 cells displayed dose-dependent improvements in motor and neurological behaviors, and reductions in infarct area and peri-infarct cell loss, much better than intravenous administration. The optimal dose was 7.5 × 106 cells/mL when delivered via the intracarotid artery within 3 days poststroke, although therapeutic effects persisted even when administered at 1 week after stroke. Compared with other mesenchymal stem cells, NCS-01 cells ameliorated both the structural and functional deficits after stroke through a broad therapeutic window. NCS-01 cells secreted therapeutic molecules, such as basic fibroblast growth factor and interleukin-6, but equally importantly we observed for the first time the formation of filopodia by NCS-01 cells under stroke conditions, characterized by cadherin-positive processes extending from the stem cells toward the ischemic cells. Collectively, the present efficacy readouts and the novel filopodia-mediated mechanism of action provide solid lab-to-clinic evidence supporting the use of NCS-01 cells for treatment of stroke in the clinical setting.