Neural stem cells exist in the developing and adult nervous systems of all mammals, but the basic mechanisms that control their behavior are not yet well understood. Here, we investigated the role of Sonic hedgehog (Shh), a factor vital for neural development, in regulating adult hippocampal neural stem cells. We found high expression of the Shh receptor Patched in both the adult rat hippocampus and neural progenitor cells isolated from this region. In addition, Shh elicited a strong, dose-dependent proliferative response in progenitors in vitro. Furthermore, adeno-associated viral vector delivery of shh cDNA to the hippocampus elicited a 3.3-fold increase in cell proliferation. Finally, the pharmacological inhibitor of Shh signaling cyclopamine reduced hippocampal neural progenitor proliferation in vivo. This work identifies Shh as a regulator of adult hippocampal neural stem cells.

SummaryBackground and objectives Translocated endotoxin derived from intestinal bacteria has a wide range of adverse effects on cardiovascular (CV) structure and function, driving systemic inflammation, atherosclerosis and oxidative stress. This study's aim was to investigate endotoxemia across the spectrum of chronic kidney disease (CKD).Design, setting, participants, & measurements Circulating endotoxin was measured in 249 patients comprising CKD stage 3 to 5 and a comparator cohort of hypertensive patients without significant renal impairment. Patients underwent extended CV assessment, including pulse wave velocity and vascular calcification. Hemodialysis (HD) patients also received detailed echocardiographic-based intradialytic assessments. Patients were followed up for 1 year to assess survival. ResultsCirculating endotoxemia was most notable in those with the highest CV disease burden (increasing with CKD stage), and a sharp increase was observed after initiation of HD. In HD patients, predialysis endotoxin correlated with dialysis-induced hemodynamic stress (ultrafiltration volume, relative hypotension), myocardial stunning, serum cardiac troponin T, and high-sensitivity C-reactive protein. Endotoxemia was associated with risk of mortality.Conclusions CKD patients are characteristically exposed to significant endotoxemia. In particular, HD-induced systemic circulatory stress and recurrent regional ischemia may lead to increased endotoxin translocation from the gut. Resultant endotoxemia is associated with systemic inflammation, markers of malnutrition, cardiac injury, and reduced survival. This represents a crucial missing link in understanding the pathophysiology of the grossly elevated CV disease risk in CKD patients, highlighting the potential toxicity of conventional HD and providing a novel set of potential therapeutic strategies to reduce CV mortality in CKD patients.

Conclusions: It was found that endotoxemia was probably common in PD patients, and the degree of circulating endotoxemia might be related to the severity of systemic inflammation and features of atherosclerosis. This result suggests that endotoxemia may have a contributory role to the systemic inflammatory state and accelerated atherosclerosis in PD patients.

Sonic hedgehog (Shh) controls critical cellular decisions between distinct fates in many systems, particularly in stem cells. The Shh network functions as a genetic switch, and we have theoretically and computationally analyzed how its structure can endow it with the ability to switch fate choices at a threshold Shh concentration. The network is composed of a positive transcriptional feedback loop embedded within a negative signaling feedback loop. Specifically, positive feedback by the transcription factor Gli, which upregulates its own expression, leads to a switch that can adopt two distinct states as a function of Shh. However, Gli also upregulates the signaling repressor Patched, negative feedback that reins in the strong Gli autoregulatory loop. Mutations that have been associated with cancer are predicted to yield an irreversible switch to a high Gli state. Finally, stochastic simulation reveals the negative Patched feedback loop serves a critical function of dampening Gli fluctuations to reduce spontaneous state switching and preserve the network's robust, switch-like behavior. Tightly linked positive and negative feedback loops are present in many signaling systems, and the Shh system is therefore likely representative of a large set of gene regulation networks that control stem cell fate throughout development and into adulthood.