Despite the high prevalence and major negative impact of uterine fibroids (UFs) on women's health, their pathogenesis remains largely unknown. While tumor-initiating cells have been previously isolated from UFs, the cell of origin for these tumors in normal myometrium has not been identified. We isolated cells with Stro1/CD44 surface markers from normal myometrium expressing stem cell markers Oct-4/c-kit/nanog that exhibited the properties of myometrial stem/progenitor-like cells (MSCs). Using a murine model for UFs, we showed that the cervix was a hypoxic "niche" and primary site (96%) for fibroid development in these animals. The pool size of these MSCs also responded to environmental cues, contracting with age and expanding in response to developmental environmental exposures that promote fibroid development. Translating these findings to women, the number of MSCs in unaffected human myometrium correlated with risk for developing UFs. Caucasian (CC) women with fibroids had increased numbers of MSCs relative to CC women without fibroids, and African-American (AA) women at highest risk for these tumors had the highest number of MSCs: AA-with fibroids > CC-with fibroids > AA-without fibroids > CC-without fibroids. These data identify Stro1 /CD44 MSCs as MSC/progenitor cell for UFs, and a target for ethnic and environmental factors that increase UF risk. Stem Cells 2017;35:666-678.

Inflammatory kidney disease is a major clinical problem that can result in end-stage renal failure. Here we show that antibody mediated inflammatory kidney injury and renal disease in a mouse nephrotoxic serum nephritis (NTN) model was inhibited by amino acid metabolism and a protective autophagic response. The metabolic signal was driven by IFN-γ-mediated induction of indoleamine 2,3 dioxygenase 1 (Ido1) enzyme activity with subsequent activation of a stress response dependent on the eIF2α kinase general control nonderepressible 2 (GCN2). Activation of GCN2 suppressed proinflammatory cytokine production in glomeruli and reduced macrophage recruitment to the kidney during the incipient stage of antibody induced glomerular inflammation. Further, inhibition of autophagy or genetic ablation of Ido1 or Gcn2 converted antibody-induced, self-limiting nephritis to fatal end-stage renal disease. Conversely, increasing kidney IDO1 activity or treating mice with a GCN2 agonist induced autophagy and protected mice from nephritic kidney damage. Finally kidney tissue from patients with antibody-driven nephropathy showed increased IDO1 abundance, GCN2 activation and autophagy induction. Thus, these findings support the hypothesis that the IDO-GCN2 pathway in glomerular stromal cells is a critical negative feedback mechanism that limits inflammatory renal pathology by inducing autophagy.

Exogenous brain-derived neurotrophic factor (BDNF) can regulate behavioral sensitization and conditioned place preference (CPP) when animals are exposed to repeated cocaine administration. However, it is unclear whether BDNF signaling through the TrkB receptor can mediate these behavioral responses when animals are given a single cocaine exposure. Because TrkB knockout mice die as neonates, we engineered a transgenic mouse that expressed a dominant negative form of TrkB (dnTrkB) in a conditional and reversible manner. We assessed also activation of endogenous TrkB by quantifying levels of phosphorylated TrkB (p-TrkB) in the nucleus accumbens (NAc). We found that a single exposure to cocaine was sufficient to increase p-TrkB within the NAc 9–12 h after administration. Expression of the dnTrkB transgene not only prevented the acute cocaine-induced increase in p-TrkB, but it also prevented behavioral sensitization and CPP following a single cocaine injection. These findings demonstrate that TrkB activation is required both for behavioral sensitization and CPP to a single cocaine exposure. The fact that enhanced TrkB activation is induced within 9 h of a single injection of cocaine suggests that inhibition of TrkB signaling commencing hours after cocaine exposure may prevent at least the initial antecedents to the sensitizing and reinforcing effects of this psychostimulant.