STAT3 dictates ß-cell apoptosis by modulating PTEN in streptozocin-induced hyperglycemia.

Insufficient pancreatic ß-cell mass or insulin-producing ß-cells are implicated in all forms of diabetes mellitus. However, the molecular mechanisms underlying ß-cell destruction are complex and not fully defined. Here we observed that activation of STAT3 is intensely and specifically inhibited in ß-cells under hyperglycemic conditions. By knocking out STAT3 specifically in mouse ß-cells, we found that the loss of STAT3 sensitized mice to three low doses of STZ stimulation resulting in hyperglycemia. Mechanistically, accumulating PTEN, induced by STAT3 deficiency, directly represses phosphorylation of AKT, which negatively modulates transcription factor activation, dysregulates ß-cell function, positively promotes apoptotic signaling, and finally induces ß-cell apoptosis. Notably, the defective secretion of insulin and ß-cells apoptosis was completely rescued by PTEN ablation in STAT3-null islets or PTEN inhibitor bpv(phen) treatment. Thus our data suggest that STAT3 is a vital modulator of ß-cell survival and function, highlighting a critical role for STAT3 in the negative regulation of PTEN-AKT signaling pathway associated with ß-cell dysfunction and apoptosis.

RIPK3 interactions with MLKL and CaMKII mediate oligodendrocytes death in the developing brain.

Oligodendrocyte progenitor cells (OPCs) death is a key contributor to cerebral white matter injury (WMI) in the developing brain. A previous study by our group indicated that receptor-interacting proteins (RIPs) are crucial in mediating necroptosis in developing neurons. However, whether this mechanism is involved in OPCs death is unclear. We aimed to explore the mechanisms of RIP-mediated oligodendrocytes (OLs) death in the developing brain. Oligodendrocytes necroptosis was induced by oxygen-glucose deprivation plus caspase inhibitor zVAD treatment (OGD/zVAD) in vitro. Western blotting and immunofluorescence were used to detect RIPK1, RIPK3, mixed lineage kinase domain-like protein (MLKL), and Ca2+ and calmodulin-dependent protein kinase IIδ (CaMKIIδ). Immunoprecipitation was used to assess the interactions between RIPK3 and RIPK1, MLKL, and CaMKIIδ. Necrostatin-1 was used to disturb the RIPK3-RIPK1 interaction, and siRNA was used to inhibit RIPK3 or MLKL expression. Oligodendrocytes death was examined using PI staining, EM, and cell membrane leakage assays. In vivo, brain damage in neonatal rats was induced by hypoxia-ischemia (HI). This was followed by an examination of myelin development. We found that OGD/zVAD treatment upregulates the expression of RIPK3 and the interaction of RIPK3 with RIPK1, MLKL, and CaMKIIδ. Inhibition of the RIPK3-MLKL or RIPK3-CaMKIIδ interaction attenuates OLs death induced by OGD/zVAD. These protective mechanisms involve the translocation of MLKL to the OLs membrane, and the phosphorylation of CaMKIIδ. However, inhibition of the RIPK3-RIPK1 interaction did not protect OLs death induced by OGD/zVAD. In vivo studies indicated that the disrupted development of myelin was attenuated after the inhibition of RIPK3-MLKL or RIPK3-CaMKIIδ interaction. Taken together, our data indicate that RIPK3 is a key factor in protection against OLs death and abnormal myelin development via its interaction with MLKL and CaMKIIδ after HI. This suggests that RIPK3 may be a potential target for the treatment of WMI in neonates.

Oligodendrocyte progenitor programming and reprogramming: Toward myelin regeneration.

Demyelinating diseases such as multiple sclerosis (MS) are among the most disabling and cost-intensive neurological disorders. The loss of myelin in the central nervous system, produced by oligodendrocytes (OLs), impairs saltatory nerve conduction, leading to motor and cognitive deficits. Immunosuppression therapy has a limited efficacy in MS patients, arguing for a paradigm shift to strategies that target OL lineage cells to achieve myelin repair. The inhibitory microenvironment in MS lesions abrogates the expansion and differentiation of resident OL precursor cells (OPCs) into mature myelin-forming OLs. Recent studies indicate that OPCs display a highly plastic ability to differentiate into alternative cell lineages under certain circumstances. Thus, understanding the mechanisms that maintain and control OPC fate and differentiation into mature OLs in a hostile, non-permissive lesion environment may open new opportunities for regenerative therapies. In this review, we will focus on 1) the plasticity of OPCs in terms of their developmental origins, distribution, and differentiation potentials in the normal and injured brain; 2) recent discoveries of extrinsic and intrinsic factors and small molecule compounds that control OPC specification and differentiation; and 3) therapeutic potential for motivation of neural progenitor cells and reprogramming of differentiated cells into OPCs and their likely impacts on remyelination. OL-based therapies through activating regenerative potentials of OPCs or cell replacement offer exciting opportunities for innovative strategies to promote remyelination and neuroprotection in devastating demyelinating diseases like MS. This article is part of a Special Issue entitled SI:NG2-glia(Invited only).