Epo receptor signaling in macrophages alters the splenic niche to promote erythroid differentiation.

Anemic stress induces stress erythropoiesis, which rapidly generates new erythrocytes to restore tissue oxygenation. Stress erythropoiesis is best understood in mice where it is extramedullary and occurs primarily in the spleen. However, both human and mouse stress erythropoiesis use signals and progenitor cells that are distinct from steady-state erythropoiesis. Immature stress erythroid progenitors (SEPs) are derived from short-term hematopoietic stem cells. Although the SEPs are capable of self-renewal, they are erythroid restricted. Inflammation and anemic stress induce the rapid proliferation of SEPs, but they do not differentiate until serum erythropoietin (Epo) levels increase. Here we show that rather than directly regulating SEPs, Epo promotes this transition from proliferation to differentiation by acting on macrophages in the splenic niche. During the proliferative stage, macrophages produce canonical Wnt ligands that promote proliferation and inhibit differentiation. Epo/Stat5-dependent signaling induces the production of bioactive lipid mediators in macrophages. Increased production of prostaglandin J2 (PGJ2) activates peroxisome proliferator-activated receptor γ (PPARγ)-dependent repression of Wnt expression, whereas increased production of prostaglandin E2 (PGE2) promotes the differentiation of SEPs.

Yap1 promotes proliferation of transiently amplifying stress erythroid progenitors during erythroid regeneration.

In contrast to steady-state erythropoiesis, which generates new erythrocytes at a constant rate, stress erythropoiesis rapidly produces a large bolus of new erythrocytes in response to anemic stress. In this study, we illustrate that Yes-associated protein (Yap1) promotes the rapid expansion of a transit-amplifying population of stress erythroid progenitors in vivo and in vitro. Yap1-mutated erythroid progenitors failed to proliferate in the spleen after transplantation into lethally irradiated recipient mice. Additionally, loss of Yap1 impaired the growth of actively proliferating erythroid progenitors in vitro. This role in proliferation is supported by gene expression profiles showing that transiently amplifying stress erythroid progenitors express high levels of genes associated with Yap1 activity and genes induced by Yap1. Furthermore, Yap1 promotes the proliferation of stress erythroid progenitors in part by regulating the expression of key glutamine-metabolizing enzymes. Thus, Yap1 acts as an erythroid regulator that coordinates the metabolic status with the proliferation of erythroid progenitors to promote stress erythropoiesis.

GATA Factor-Regulated Samd14 Enhancer Confers Red Blood Cell Regeneration and Survival in Severe Anemia.

An enhancer with amalgamated E-box and GATA motifs (+9.5) controls expression of the regulator of hematopoiesis GATA-2. While similar GATA-2-occupied elements are common in the genome, occupancy does not predict function, and GATA-2-dependent genetic networks are incompletely defined. A "+9.5-like" element resides in an intron of Samd14 (Samd14-Enh) encoding a sterile alpha motif (SAM) domain protein. Deletion of Samd14-Enh in mice strongly decreased Samd14 expression in bone marrow and spleen. Although steady-state hematopoiesis was normal, Samd14-Enh-/- mice died in response to severe anemia. Samd14-Enh stimulated stem cell factor/c-Kit signaling, which promotes erythrocyte regeneration. Anemia activated Samd14-Enh by inducing enhancer components and enhancer chromatin accessibility. Thus, a GATA-2/anemia-regulated enhancer controls expression of an SAM domain protein that confers survival in anemia. We propose that Samd14-Enh and an ensemble of anemia-responsive enhancers are essential for erythrocyte regeneration in stress erythropoiesis, a vital process in pathologies, including ß-thalassemia, myelodysplastic syndrome, and viral infection.

Protective effects of ethanol extract from Portulaca oleracea L on dextran sulphate sodium-induced mice ulcerative colitis involving anti-inflammatory and antioxidant.

Portulaca oleracea L., (POL) is one of commonly used medicine-food herbs and has a cosmopolitan distribution in many countries. Many studies showed that POL exhibited a wide range of pharmacological effects such as anti-inflammatory and liver complaints. In the clinical studies, POL was usually used for the treatment of UC disease and the clinical efficacy was well, but the mechanism and scientific intension was still unknown. In the present study, we studied the protective effects of the ethanol extract from POL on dextran sulphate sodium-induced UC in C57BL/6 mice model through oxidative stress and inflammatory pathway. The results demonstrated that the ethanol extract from POL could exhibit the effective protection for the DSS induced UC by increasing the colon length, decreasing body weight loss and the disease activity index score, inhibiting oxidative stress response through the MDA, NO, SOD activities, reducing the mRNA expressions of pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6) and the protein expressions of TNF-α and NF-kB p65. These results may prove that POL could be considered as a useful and effective botanical compound from the edible plant to be used in UC through the oxidative stress and inflammatory activities.