In the July 17th online early edition of Cell Stem Cell, P. Charbord et al. INSERM (Villejuif, France) reported their experimental findings on the molecular requirements for supporting the hematopoietic stem/progenitor cell (HSPC) niches. The investigators conducted transcriptome meta-analysis on a panel of six HSPC stromal cell lines from embryonic and adult tissues that were either supportive or less-supportive of the hematopoietic niche. The experimental data 481 mRNAs transcripts and 17 microRNAs in a modular network indicative of paracrine signaling and HSPC support by stromal cells without cell-cell contact. Functional studies in zebrafish embryos confirmed the gene set of niche support which consisted of known HSPC regulators such as Pax9 and Ccdc80. The authors concluded that their study results "identified the core molecular network required for HSPC support."
In the July 24th online advance publication of Cell Stem Cell, Th. Theunissen et al. from MIT's Whitehead Institute published their study results on identifying small molecules which support the "naive state" of pluripotency in human embryonic stem cells (hESCs). The investigators used a TALEN-mediated engineering reporter system for screening a chemical library to identify compounds which can maintain endogenous OCT4 distal enhancer activity associated with the ground state of hESCs. Experimental results revealed a combination of "five kinase inhibitors that induces and maintains OCT4 distal enhancer activity." In vitro, the inhibitors were found to upregulate ground state transcription factors associated with pluripotency concomitant with a decrease in bivalent chromatin domains. Gene expression profile of naive human cells were very similar to that of naive murine cells. The authors concluded their experimental results provide a "framework for defining culture requirements of naive human pluripotent cells."
In the July 24th online advance publication of Cell Stem Cell, Th. Theunissen et al. from MIT's Whitehead Institute published their study results on identifying small molecules which support the "naive state" of pluripotency in human embryonic stem cells (hESCs). The investigators used a TALEN-mediated engineering reporter system for screening a chemical library to identify compounds which can maintain endogenous OCT4 distal enhancer activity associated with the ground state of hESCs. Experimental results revealed a combination of "five kinase inhibitors that induces and maintains OCT4 distal enhancer activity." In vitro, the inhibitors were found to upregulate ground state transcription factors associated with pluripotency concomitant with a decrease in bivalent chromatin domains. Gene expression profile of naive human cells were very similar to that of naive murine cells. The authors concluded their experimental results provide a "framework for defining culture requirements of naive human pluripotent cells."
In the July 23rd issue of the Journal of Neuroscience, G. Lewandowski & O. Steward from the University of California, Irvine reported their study results on regenerating corticospinal axons after spinal cord injury (SCI). The investigators used a gene therapy approach by injecting intracortically into rats adeno-associated virus as a vector carrying the gene encoding for shRNA (AAVsh) which inhibits the expression of phosphatase and tensin homolog (PTEN/AAVshPTEN). Rats receiving AAVshPTEN alone were found not to exhibit improved motor function following cervical dorsal hemisection injuries (SCI) 10 weeks after the injury. However, the group receiving AAVshPTEN concomitant with injection of salmon fibrin at the injury site were shown to have improved motor function with significantly higher forelimb-reaching scores. Additionally, the group receiving AAVshPTEn and salmon fibrin had axons extending further caudally in the corticospinal tract (CST) than the controls or group receiving only AAVshPTEN. The authors concluded from their study observations that their "data suggest that the combination of PTEN deletion and salmon fibrin injection into the lesion can significantly improve voluntary motor function after SCI by enabling regenerative growth of CST axons."
In the June 5th online early publication of Medicine & Science in Sports & Exercise, K. Zou et al. from the University of Illinois reported their study results on mesenchymal stems rejuvenating skeletal muscle after resistance exercise in mice. The investigators had found that transgenic (Tg) mice overexpressing the transmembrane protein α7B integrin enhanced satellite cell and growth response to eccentric exercise. Muscle mesenchymal stem cells (mMSCs/Sca1+CD45-) isolated from α7Tg mice were dye-labeled and injected into skeletal muscle of wild type recipient mice. Post-injection the mice were either sedentary or subjected to eccentric exercise training (downhill running) on a treadmill 3X/week. The experimental results demonstrated that mMSCs did not directly fuse with existing muscle fiber but enhanced Pax7+ cell numbers and myonuclear content in existing muscle fibers in the group undergoing eccentric exercise training. Also, rip strength improved in the exercise group. However, mMSC transplantation did not enhance tissue repair and growth in the absence of exercise. The authors concluded from their study that "mMSCs contribute to beneficial changes in satellite cell expansion and growth in α7Tg muscle following eccentric exercise. Thus, MSCs that naturally accumulate in muscle following eccentric contractions may enhance the adaptive response to exercise."
In the April 22nd online advance publication of Cell Transplantation, S. Dhingra et al. from the University of Toronto published their study results on transduction of allogeneic smooth muscle cells (SMCs) with Interleukin -10 (IL-10) gene to enhance engraftment in a rat model with experimental-induced myocardial infarction. The investigators used three groups of rats injected into the infarct site with either unmodified autologous, unmodified allogeneic, or allogeneic smooth muscle cells transduced with IL-10 gene. In vitro and in vivo results demonstrated that SMCs expressing IL-10 increased the number of regulatory T cells (CD4+CD25+) and reduced the number of cytotoxic T cells (CD8+) concomitant with a reduction in the anti-allogeneic antibody response. Transplantation of both unmodified autologous SMCs and modified allogeneic SMCs were shown to improve ventricular function (fractional shortening) and left ventricular dimensions (wall thickness) compared to the control or unmodified allogeneic SMCs. The researchers also reported enhanced survival in the groups receiving unmodified autologous SMCs and modified allogeneic SMCs. The authors concluded from their study observations "that IL-10 gene therapy with allogeneic SMCs prevents detrimental allo-immune response in the recipient, thereby increasing the survival of transplanted allogeneic SMCs and more effectively restoring cardiac function."
In the July 17th online edition of Cell Reports, M. Foronda et al. from the Spanish National Cancer Research Centre (CNIO) published heir experimental results on dissecting the regulatory of Sox4 expression in normal tissue replacement, cancer, and aging. In mammals, Sox4 expression is restricted to the development of embryonic tissues and some adult tissues such as lymphoid, pancreas, intestine, and skin. The investigators were able to generate mice with reduced whole body expression of Sox4. In Sox4-deficient mice, they were found to be resistant to cancer with accelerated aging. However, aberrant Sox4 expression was linked to malignant transformation and metastasis in several types of cancer. Conditional deletion of Sox4 in stratified epithelial leads to stem cell quiescence and skin damage concomitant with a "downregulation of the cell cycle, DNA repair, and activated hair follicle stem cell pathways." The researches performed expression analysis and found Sox4 to be involved in the β-catenin/Wnt signaling pathway during hair follicle stem cell activation. The authors concluded from their study results that Sox4 has an important role "in regulating adult tissue homeostasis and cancer."
Category: General
In the July 15th advanced publication of Cell Transplantation, S. M. Jonsdottir-Buch et al. from the University of Iceland (Reykjavik, Iceland) published their study results on used expired platelet concentrates for generating platelet lysates as a supplement for culturing bone marrow-derived mesenchymal stem cells (MSCs). The investigators determined immunodmodulation, immunophenotype, proliferation and trilineage differentiation of MSCs cultured in media supplemented with aged, UV-irradiated platelet lysates. The experimental results showed that platelet lysates from expired, pathogen inactivate platelet concentrates supported MSC differentiation and its immunosuppressive properties better than platelet lysates prepared from expired platelet units. The authors concluded that "the use of expired pathogen-inactivated platelet units from blood banks to prepare platelet lysates for the culture of MSCs is desirable and attainable."
Category: Reprogramming
In the July 7th online advance publication of Science, E. Gonzalez-Munoz et al. from Michigan State University reported their experimental results on identifying a gene involved in reprogramming somatic cells into induced pluripotent stem cells (iPSCs). The investigators found from analyzing over 5000 genes expressed in human oocytes that the histone-remodeling chaperone protein, ASF1A, is enriched in human oocytes during metaphase II (MII). ASF!A was found to be essential for reprogramming human adult fibroblasts (hADFs) into iPSCs. Additionally, ASF1A and Oct4 concomitant with the oocyte-specific paracrine factor GDF9, as a helper soluble molecule, were responsible for reprogramming terminally differentiate somatic cells into iPSCs. The authors concluded from their experimental observations that studying unfertilized oocyte in MII is an important cell source for providing "a greater understanding of the molecular pathways governing somatic cell reprogramming."
In the July 10th online advanced publication of Cell Stem Cell, M. Hanoun et al. from Albert Einstein College Medicine reported their study results on the effects of acute myelogenous leukemia stem cells the bone marrow microenvironment. Using a AML mouse model (MLL-AF9), the investigators found that neuropathy of the sympathetic nervous system (SNS) promotes leukemic bone marrow infiltration. AML disease progression disrupts the SNS nerves and the quiescent Nestin+ cells within the bone marrow niche. The altered bone marrow microenvironment leads to expansion of mesenchymal stem and progenitor cells (MSPCs) which results in enhanced differentiation towards osteoprogenitors. AML also results in a reduction in the number of NG2+ periarteriolar niche cells which regulate the HSC niche. The experimental data also revealed that neuropathy of the SNS promotes AML by adrenergic signaling through the β3 adrenergic receptor on the stromal cells. The authors concluded that their study results "indicate that sympathetic neuropathy may represent a mechanism for the malignancy in order to co-opt the microenvironment and suggest separate mesenchymal niche activities for malignant and healthy hematopoietic stem cells in the bone marrow."