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Objective(s): Hematopoietic stem cells (HSCs) are the cells that give rise to different types of blood cells during the hematopoiesis process. Mesenchymal stromal cells (MSCs) as key elements in the bone marrow (BM) niche interact with hematopoietic progenitor cells (HPCs) by secreting cytokines, which control HPCs maintenance and fate. Here we report that BM-MSCs are capable of inducing granulocytic differentiation of the C-Kit+ HSCs via activating JAK3/STAT3, ERK, and PI3K signaling pathways. Materials and Methods: For this purpose, BM-MSCs and C-kit+ HSCs were isolated. Next, cells were divided into two groups and differentiated into granulocytes: C-kit+ HSCs alone (control group) and co-cultured C-kit+ HSCs with MSCs (experimental group). Afterward, the gene and protein expression were assessed by real-time PCR and western blotting, respectively. Results: It was found that BM-MSCs resulted in increased JAK3/STAT3, ERK, and PI3K protein expression in granulocyte differentiated C-kit+ HSCs. Conclusion: It should be concluded that MSCs could affect the granulocyte differentiation of C-kit+ HSCs via increasing JAK3/STAT3, ERK, and PI3K signaling pathways. [ABSTRACT FROM AUTHOR]

After loss of intestinal surface area, the remaining bowel undergoes a morphometric and functional adaptive response. Enterocytic expression of the transcriptional coregulator tetradecanoyl phorbol acetate induced sequence 7 (Tis7) is markedly increased in a murine model of intestinal adaptation. Mice overexpressing Tis7 in intestine have greater triglyceride absorption and weight gain when fed a high-fat diet (42% energy) than their wild-type (WT) littermates fed the same diet. These and other data suggest that Tis7 has a unique role in nutrient absorptive and metabolic adaptation. Herein, male [Tis7.sup.-/-] and WT mice were fed a high-fat diet (42% energy) for 8 wk. Weight was monitored and metabolic analyses and hepatic and intestinal lipid concentrations were compared after 8 wk. Intestinal lipid absorption and metabolism studies and intestinal resection surgeries were performed in separate groups of [Tis7.sup.-/-] and WT mice. At 8 wk, weight gain was less and jejunal mucosal and hepatic triglyceride and cholesterol concentrations were lower in [Tis7.sup.-/-] mice than in the WT controls. Following corn oil gavage, serum cholesterol, triglyceride, and FFA concentrations were lower in the [Tis7.sup.-/-] mice than in the WT mice. Incorporation of oral [sup.3][H] triolein into intestinal mucosal cholesterol ester and FFA was less in [Tis7.sup.-/-] compared with WT mice. Following resection, crypt cell proliferation rates and villus heights were lower in [Tis7.sup.-/-] than in VVT mice, indicating a blunted adaptive response. Our results suggest a novel physiologic function for Tis7 in the gut as a global regulator of lipid absorption and metabolism and epithelial cell proliferation. J. Nutr. 140: 1907-1914, 2010. doi: 10.3945/jn.110.127084.

Lung disease is the major cause of morbidity and mortality in cystic fibrosis, an autosomal recessive disease caused by mutations in CFTR. In cystic fibrosis, chronic infection and dysregulated neutrophilic inflammation lead to progressive airway destruction. The severity of cystic fibrosis lung disease has considerable heritability, independent of CFTR genotype (1). To identify genetic modifiers, here we performed a genome-wide single nucleotide polymorphism scan in one cohort of cystic fibrosis patients, replicating top candidates in an independent cohort. This approach identified IFRD1 as a modifier of cystic fibrosis lung disease severity. IFRD1 is a histone-deacetylase-dependent transcriptional co-regulator expressed during terminal neutrophil differentiation. Neutrophil, but not macrophages, from Ifrd1-deficient mice showed blunted effector function, associated with decreased NF-κB p65 transactivation. In vivo, IFRD1 deficiency caused delayed bacterial clearance from the airway, but also less inflammation and disease--a phenotype primarily dependent on haematopoietic cell expression, or lack of expression, of IFRD1. In humans, IFRD1 polymorphisms were significantly associated with variation in neutrophil effector function. These data indicate that IFRD1 modulates the pathogenesis of cystic fibrosis lung disease through the regulation of neutrophil effector function., Attention to the role of CFTR in regulating epithelial ion transport has failed to illuminate the path from gene to pathogenesis in cystic fibrosis (CF) lung disease. In CF, colonization [...]

In recent years, several studies have investigated cell transplantation as an innovative strategy to restore cardiac function following heart failure. Previous studies have also shown cardiac progenitor cells as suitable candidates for cardiac cell therapy compared with other stem cells. Cellular kit (c-kit) plays an important role in the survival and migration of cardiac progenitor cells. Like other types of cells, in the heart, cellular responses to various stimuli are mediated via coordinated pathways. Activation of c-kit+ cells leads to subsequent activation of several downstream mediators such as PI3K and the MAPK pathways. This review aims to outline current research findings on the role of PI3K/AKT and the MAPK pathways in myocardial regeneration potential of c-kit+. [ABSTRACT FROM AUTHOR]

Late endosomal/lysosomal adaptor and MAPK and mTOR activator (LAMTOR/Ragulator) is a scaffold protein complex that anchors and regulates multiprotein signaling units on late endosomes/lysosomes. To identify LAMTOR‐modulated endolysosomal proteins, primary macrophages were derived from bone marrow of conditional knockout mice carrying a specific deletion of LAMTOR2 in the monocyte/macrophage cell lineage. Affymetrix‐based transcriptomic analysis and quantitative iTRAQ‐based organelle proteomic analysis of endosomes derived from macrophages were performed. Further analyses showed that LAMTOR could be a novel regulator of foam cell differentiation. The lipid droplet formation phenotype observed in macrophages was additionally confirmed in MEFs, where lipidomic analysis identified cholesterol esters as specifically downregulated in LAMTOR2 knockout cells. The data obtained indicate a function of LAMTOR2 in lipid metabolism. [ABSTRACT FROM AUTHOR]

The idea of regenerating lost myocardium via cell-based therapies remains as highly considerable. C-kit+ stem/progenitor cells are represented to be suitable candidates for cardiac regeneration compared to other stem cells. A multitude of cytokines from these cells are known to give such multifunctional properties; however, the associated mechanisms of these factors are yet to be totally understood. The aim of the present study was to investigate the in vitro effect of L-carnitine (LC) on cardiac differentiation of c-kit+ cells using a cytokines secretion assay. For this purpose, bone-marrow-resident-c-kit+ cells were enriched by MACS method, and were differentiated to cardiac cells using cardiomyocyte differentiation medium in the absence (control group) and presence of LC (experimental group). Also, characterization of enriched c-kit+ cells was performed using flow cytometry and immunocytochemistry. In the following, the cells were subjected to real-time PCR and Western blotting assay for gene and protein assessment, respectively. Afterward, culture medium was collected from both control (−LC) and experimental groups (+ LC) for cytokine measurement. It was found that 0.2 mM LC significantly increased the mRNA and protein expression of cardiac markers of Ang-1, Ang-2, C-TnI, VEGF, vWF, and SMA in c-kit+-cardiomyogenic-differentiated cells. Also, the significant presence of IL-6, IGF-1, TGF-β, and VEGF were obvious in the cultured media from the experimental group compared with the control group. It can be concluded that the mentioned in vitro effects of LC on cardiac differentiation of c-kit+ cells could have resulted from the secreted cytokines IL-6, IGF-1, TGF-β, and VEGF. [ABSTRACT FROM AUTHOR]

Background: Increased oxygen species levels can induce mitochondrial DNA damage and chromosomal aberrations and cause defective stem cell differentiation, leading finally to senescence of stem cells. In recent years, several studies have reported that antioxidants can improve stem cell survival and subsequently affect the potency and differentiation of these cells. Finding factors, which reduce the senescence tendency of stem cells upon expansion, has great potential for cellular therapy in regenerative medicine. This study aimed to evaluate the effects of L-carnitine (LC) on the aging of C-kit+ hematopoietic progenitor cells (HPCs) via examining the expression of some signaling pathway components., Methods: For this purpose, bone marrow resident C-kit+ HPCs were enriched by the magnetic-activated cell sorting (MACS) method and were characterized using flow cytometry as well as immunocytochemistry. Cells were treated with LC, and at the end of the treatment period, the cells were subjected to the realtime PCR technique along with a western blotting assay for measurement of the telomere length and assessment of protein expression, respectively., Results: The results showed that 0.2 mM LC caused the elongation of the telomere length and increased the TERT protein expression. In addition, a significant increase was observed in the protein expression of p38, p53, BCL2, and p16 as key components of the telomere-dependent pathway., Conclusion: It can be concluded that LC can increase the telomere length as an effective factor in increasing the cell survival and maintenance of the C-kit+ HPCs via these signaling pathway components., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)