In the August 17th issue of Developmental Cell, Y. Ishii et al. from the Univ. of Calif., San Francisco reported their observations on the expression of BMP ligands in the embryonic myocardium regulate the migration of epicardial progenitors to the heart. The investigators noted that the extracardiac rudiment, the procardium, gives rise to corOnonary vessels and the epicardium of the heart during development. The mechanism in which the procardium protrudes toward and attaches to the looping heart tube appears to be mediated by ecotopic expression of BMP 2/4. The study data demonstrated that misexpression of the BMP ligands suppresses proepicardium protrusion in the developing heart whcih results in mislocation of proepicardium attachment. Further, the BMP antagonist, Noggin, suppresses proepicardium protrusion. Co-culture experiments revealed that procardium explants preferentially expands toward the heart segment expressing BMP 2/4. The authors concluded that their study results support their model "in which myocardium-derived BMP signals regulate the entry of coronary progenitors to the specific site of the heart by directing their morphogenetic movement."

In the August 9th issue of Cell Stem Cell, K. V. Pajcini et al. from Stanford University School of Medicine reported their study results that a tumor suppressor which apparent represses tissue regeneration in mammals. The investigators found that by inactivating Arf and Rb (Ink4a product and tumor suppressor, respectively) in single isolated myocytes, the blocked cells in vitro formed myoblast colonies. The ex vivo expanded myoblasts were able to differentiate and fuse into myofibes upon transplantation. The authors concluded from their study results that "differentiation of mammalian cells is reversed by inactivation of Arf and Rb and support the hypothesis that Arf evolved at the expense of regeneration."

In the August 17th issue of Developmental Cell, T. Spruce et al. from the Imperial College of London reported their study results on the role of miRNAs in the maintenance of embryonic stem cells during very early development of the mouse embryo (i.e. embryonic, epiblast, trophoblast, and primitive endoderm). The investigators found that in the miRNA inhibit apoptosisin pluripotent epiblasts by blocking the expression of the pro-apoptotic protein Bcl2l11 (Bim). The study data also demonstrated that miRNAs maintain the trophoblast stem cell compartment by inhibiting expression of Cdkn1a (p21). Additionally, blocking the expression of Mapk inhibitors by miRNAs maintains the phosphorylated state of ERK1/2 and preventing differentiation. The authors concluded that "there are fundamental differences in how stem cells maintain their developmental potential in embryonic and extraembryonic tissues through miRNAs."

In the August 19th online edition of Cell Stem Cell, J. Tchieu et al. from the UCLA School of Medicine reported their study results on epigenetic modication and X chromosome inactivation in human reprogrammed fibroblasts. The investigators noted that reprogramming of female mouse cells results in reactivation of the inactive X chromosome (Xi). However, the researchers found that in human induced pluripotent stem cells (hiPSCs) several of the female cell lines carried the inactive X chromosome. The experimental data revealed that Xi chromatin did undergo some epigenetic modifications since there was only partial loss of the XIST transcripts as opposed to female human embryonic stem cell lines in which exhibit two active X chromosomes. Additionally, the human female fibroblasts are mosaics for Xi, whereas hiPSCs are clonal. The authors noted that "the nonrandom pattern of X chromosome inactivation in female hiPSCs, which is maintained upon differentiation, has critical implications for clinical applications and disease modeling, and could be exploited for a unique form of gene therapy for X-linked diseases."

In the August 23rd online edition of Stem Cells, Q-Z. Zhang et al. from the Univ. of Southern California School of Dentistry reported their study on mesenchymal stem cells isolated from human gingiva (GMSCs) and their role in skin wound healing. The investigators found that when they co-cultured GMSCs with macrophages, the phagocytic cells acquired an anti-inflammatory M2 phenotype in which the cells exhibited upregulation of the mannose receptor (MR/CD206), IL-6, and IL-10. Co-culturing with GMSCs also reduced the production of TNF-α as well as decreased the ability to induce Th17 cell expansion. In vivo experiments demonstrated that infused GMSCs homed to the wound site and converted the host macrophages toward a M2 phenotype that significantly enhanced wound healing. Enhanced cutaneous healing was attributed to donor GMSCs reducing local inflammation by suppressing both production of IL-6 and TNF-α and infiltration of inflammatory cells concomitant with increased production of IL-10. The researchers also provided data supporting the observation of GMSC suppression of macrophages to secrete TNF-α correlated with impaired activation of NF-kβ p50 signaling pathway. The authors concluded from their study results that suggest that "GMSCs are capable to elicit M2 polarization of macrophage, which might contribute to a marked acceleration of wound healing."

Scientists from Baylor College of Medicine, R. T. Wagner et al., reported in the August 23rd online edition of Stem Cells their experimental findings on an alternative signaling pathway that regulates pluripotency in embryonic stem cells (ESCs). Pluripotency in vitro is maintained by LIF (leukemia inhibitory factor) which stimulates two signaling axes, i.e. Stat3/Klf4/Sox2 and PI3K/Tbx3/Nanog. The researchers found that their experimental data revealed that the liver receptor homolog-1 (Lrh-1) protein targets β-catenin which in turn directly regulates Nanog. The researchers noted that Lrh-1 is not only responsible for Oct4 expression, but that is was also responsible for maintaining proper levels of Nanog and Tbx3. The authors concluded that elucidation of the Lrh-1 regulator pathway "provides an alternative mechanism by which the primary pluripotency axis may be regulated in vivo, and may pave the way for small molecule applications to manipulate pluripotency, or improved the efficiency of somatic cell reprogramming."

In the August 2nd issue of Stem Cell Reviews and Reports, L. Jiang et al. from the University of South Florida reported their study on delineating in vitro the cellular component(s) in human umbilical cord blood (HUCB) which appears to have a protective effect on rat astrocytes cultured in both a hypoxiic and low glucose environment. The investigators found that astrocyte viability was enhanced by adding HUCB to hypoxic astrocyte cell cultures. With magnetic antibody cell sorting, the researchers co-culture the astrocytes with different mononuclear cell fractions to determine their effects on astrocyte survival during hypoxia. The experimental results revealed that co-culturing mononuclear cells with astrocyte stimulated IL-6 and IL-10 production during hypoxia. However, T cells isolated from cord blood and added to the astrocyte cultures decreased survival of the astroytes with no effect on cytokine production. The authors concluded from their study results that "the texted cord blood fractions do not enhance astrocyte survival when delivered individually, suggesting there is either another cellular component that is neuroprotective or an interaction of all the cells is essential for protection" during stroke/cerebral ischemia.

In the August 23rd online edition of Stem Cells, J. Zhou et al. from the University of Illinois at Urbana-Champaign reported their experimental findings in identifying a protein kinase inhibitor, compound C, which appears to be a potent regulator of fate decisions for both human embryonic stem cells (hESCS) as well as human induced pluripotent stem cells (hiPSCs). Compound C suppresses differentiation of mesoderm, endoderm, and trophoectoderm while inducing, with a high efficiency, neural conversion in both hESCs and hiPSCs (88.7% and 70.4 %, respectively). The investigators found that compound C targets at least 7 TGF-β superfamily receptors, and thus, blocks both Activing and BMP signaling in hESCs. The researchers also found that compound C targets a homeobox gene 2 (MSX2) downstream which is an intermediate in the BMP signaling pathway in hESCs. The authors concluded that their study results "provide a single-step cost-effective method for efficient derivatlon of neural progenitors cells in adherent culture from human pluripotent stem cells."

In the August 16th online edition of Stem Cells, Germany scientists from the Max Planck Institute for Molecular Biomedicine (Munster), J. Sterneckert et al., reported their study results on FGF (fibroblast growth factor) signaling mediating the induction of embryonic stem cells (ESCs) committing to a neural lineage. In vitro experiments demonstrated that neural commitment required the ESCs to differentiate into epiblast cells which required FGF signaling. Additionally, FGF2 was found to formation to inhibit neurogenesis via epiblastic intermdeiates while promoting transient self-renewal in the epiblastic stem cells in a dose-dependent fashion. On the other hand, FGF8, a known endogenous, was not able to promote epiblastic self-renewal but it could transient self-renewal of early neural stem cells. Inhibiting FGF in epiblast cells promotes rapid neural induction and subsequent neurogenesis. The authors concluded that "FGF signaling plays different roles during the differentiation of ES cells, with an initial requirement in epiblast formation and subsequent epiblast formation" as well as having an important role in self-renewal.

In the July 19th online edition of Nature, K. Kim et al. from Harvard Medical School reported their findings on methylation patterns in low-passage induced pluripotent stem cells (iPSCs). The experimental results revealed that murine iPSCs which were derived from trancription factor-based reprogramming still retain some of the methylation characteristics of their somatic tissue origin. The DNA methylation signature in these iPSCs had restricted cell fates and favored downstream differentiation into tissue lineages related to the unprogrammed donor cell. The investigators found from their experimental data that this epigenetic memory could be reset by differentiation and serial reprogramming as well as by using chromatin-modifying drugs. Additionally, pluripotent stem cells derived by somatic cell nuclear transfer had methylation patterns closely resembling "classical" embryonic stem cells. The authors concluded that their study results demonstrated that "nuclear transfer is more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modeling or treatment."