Stem cells for therapy in TBI.

While the pace of traumatic brain injury (TBI) research has accelerated, the treatment options remain limited. Clinical trials are yet to yield successful treatment options, leading to innovative strategies to overcome the severe debilitating consequences of TBI. Stem cells may act as a potential treatment option. They have two key characteristics, the ability of self-renewal and the ability to give rise to daughter cells, which in the case of neural stem cells (NSCs) includes neurons, astrocytes and oligodendrocytes. They respond to the injury environment providing trophic support and have been shown to differentiate and integrate into the host brain. In this review, we introduce the notion of an NSC and describe the two neurogenic niches in the mammalian brain. The literature supporting the activation of an NSC in rodent models of TBI, both in vivo and in vitro, is detailed. This endogenous activation of NSCs may be augmented by exogenous transplantation of NSCs. Delivery of NSCs to assist the host nervous system has become an attractive option, with either fetal or adult NSC. This has resulted in cognitive and functional improvement in rodents, and current animal studies are using human NSCs. While no NSC clinical trials are currently ongoing for TBI, this review touches upon other neurological diseases and discuss how this may move forward into TBI.

Inhibition of p38alpha MAPK disrupts the pathological loop of proinflammatory factor production in the myelodysplastic syndrome bone marrow microenvironment.

Myelodysplastic syndromes (MDS) are common causes of ineffective hematopoiesis and cytopenias in the elderly. Various myelosuppressive and proinflammatory cytokines have been implicated in the high rates of apoptosis and hematopoietic suppression seen in MDS. We have previously shown that p38 MAPK is overactivated in MDS hematopoietic progenitors, which led to current clinical studies of the selective p38alpha inhibitor, SCIO-469, in this disease. We now demonstrate that the myelosuppressive cytokines TNFalpha and IL-1beta are secreted by bone marrow (BM) cells in a p38 MAPK-dependent manner. Their secretion is stimulated by paracrine interactions between BM stromal and mononuclear cells and cytokine induction correlates with CD34+ stem cell apoptosis in an inflammation-simulated in vitro bone marrow microenvironment. Treatment with SCIO-469 inhibits TNF secretion in primary MDS bone marrow cells and protects cytogenetically normal progenitors from apoptosis ex vivo. Furthermore, p38 inhibition diminishes the expression of TNFalpha or IL-1beta-induced proinflammatory chemokines in BM stromal cells. These data indicate that p38 inhibition has anti-inflammatory effects on the bone marrow microenvironment that complements its cytoprotective effect on progenitor survival. These findings support clinical investigation of p38alpha as a potential therapeutic target in MDS and other related diseases characterised by inflammatory bone marrow failure.