Hypoxia promotes the phenotypic change of aldehyde dehydrogenase activity of breast cancer stem cells.

Stable breast cancer cell (BCC) lines are valuable tools for the identification of breast cancer stem cell (BCSC) phenotypes that develop in response to several stimuli as well as for studying the basic mechanisms associated with the initiation and maintenance of BCSCs. However, the characteristics of individual, BCC-derived BCSCs varies and these cells show distinct phenotypes depending on the different BCSC markers used for their isolation. Aldehyde dehydrogenase (ALDH) activity is just such a recognized biomarker of BCSCs with a CD44 /CD24 phenotype.

In vivo retinal and choroidal hypoxia imaging using a novel activatable hypoxia-selective near-infrared fluorescent probe.

Purpose: Retinal hypoxia plays a crucial role in ocular neovascular diseases, such as diabetic retinopathy, retinopathy of prematurity, and retinal vascular occlusion. Fluorescein angiography is useful for identifying the hypoxia extent by detecting non-perfusion areas or neovascularization, but its ability to detect early stages of hypoxia is limited. Recently, in vivo fluorescent probes for detecting hypoxia have been developed; however, these have not been extensively applied in ophthalmology.

Microvesicles derived from Alde-Low EPCs support the wound healing capacity of AT-MSCs.

Mesenchymal stem cells (MSCs) are defined as multipotent cells that can give rise to various kinds of differentiated mesenchymal cells, and are thus considered to be useful for clinical therapy. However, the big hurdles of MSC therapy are the inability of MSCs to reach the appropriate tissues or sites with high efficiency and engraftment after transplantation. In this study, we investigated how adipose tissue-derived MSCs (AT-MSCs) improve their homing ability after intravenous injection.

A Chemokine Receptor, CXCR4, Which Is Regulated by Hypoxia-Inducible Factor 2α, Is Crucial for Functional Endothelial Progenitor Cells Migration to Ischemic Tissue and Wound Repair.

Endothelial progenitor cells (EPCs) have the ability to form new blood vessels and protect ischemic tissues from damage. We previously reported that EPCs with low activity of aldehyde dehydrogenase (Alde-Low EPCs) possess the greater ability to treat ischemic tissues compared with Alde-High EPCs. The expression level of the hypoxia-inducible factors (HIFs), HIF-1α and HIF-2α, was found to be greater in Alde-Low EPCs than in Alde-High EPCs.

Hypoxia-inducible factor-3α promotes angiogenic activity of pulmonary endothelial cells by repressing the expression of the VE-cadherin gene.

The variants of the hypoxia-inducible factor-3α gene HIF-3α and NEPAS are known to repress the transcriptional activities driven by HIF-1α and HIF-2α. Although NEPAS has been shown to play an important role in vascular remodeling during lung development, little is known about the roles of HIF-3α in adult lung function. Here, we examined pulmonary endothelial cells (ECs) isolated from wild-type (WT) and HIF-3α functional knockout (KO) mice.

Impaired expression of HIF-2α induces compensatory expression of HIF-1α for the recovery from anemia.

Erythropoiesis is strongly influenced by the interactions between stromal cells and erythroid progenitors, as well as by a key regulatory factor, erythropoietin (EPO). We previously generated mice with a knockdown mutation of Hif-2α (referred to as kd/kd) and found that these kd/kd mice exhibited normocytic anemia, even though the EPO expression was not severely affected. However, the VCAM-1 expression in spleen endothelial cells (EC), which is regulated by HIF-2α, was impaired, resulting in defective erythroid maturation.

The role of CCL5 in the ability of adipose tissue-derived mesenchymal stem cells to support repair of ischemic regions.

Mesenchymal stem cells (MSC) are multipotent and possess high proliferative activity, and thus are thought to be a reliable cell source for cell therapies. Here, we isolated MSC from adult tissues--bone marrow (BM-MSC), dental tissue (DT-MSC), and adipose tissue (AT-MSC)--to compare how autotransplantation of these MSC effectively supports the repair of bone fracture and ischemic tissue. An analysis by in vitro differentiation assays showed no significant difference among these MSC.

Functional endothelial progenitor cells selectively recruit neurovascular protective monocyte-derived F4/80(+) /Ly6c(+) macrophages in a mouse model of retinal degeneration.

Retinitis pigmentosa is a group of inherited eye disorders that result in profound vision loss with characteristic retinal neuronal degeneration and vasculature attenuation. In a mouse model of retinitis pigmentosa, endothelial progenitor cells (EPC) from bone marrow rescued the vasculature and photoreceptors. However, the mechanisms and cell types underlying these protective effects were uncertain.

Umbilical cord blood-derived mesenchymal stem cells inhibit, but adipose tissue-derived mesenchymal stem cells promote, glioblastoma multiforme proliferation.

Mesenchymal stem cells (MSCs) possess self-renewal and multipotential differentiation abilities, and they are thought to be one of the most reliable stem cell sources for a variety of cell therapies. Recently, cell therapy using MSCs has been studied as a novel therapeutic approach for cancers that show refractory progress and poor prognosis. MSCs from different tissues have different properties.

A subpopulation of endothelial progenitor cells with low aldehyde dehydrogenase activity attenuates acute ischemic brain injury in rats.

Previous studies have examined the therapeutic effect of endothelial progenitor cells (EPCs) during the chronic phase of cerebral infarction in rats; however, few studies have investigated the effects of EPCs during the acute phase of infarction. In this study, we evaluated the therapeutic effect of EPCs with low aldehyde dehydrogenase activity (Alde-Low EPCs) in rats with acute cerebral infarction, and our results provide insight that may help to identify a therapeutic mechanism of EPCs for acute cerebral infarction. The administration of Alde-Low EPCs into rats with acute cerebral infarction results in the accumulation and migration of the Alde-Low EPCs into the infarct area and the subsequent decrease of infarct volume.

Identification of human placenta-derived mesenchymal stem cells involved in re-endothelialization.

Human placenta is an attractive source of mesenchymal stem cells (MSC) for regenerative medicine. The cell surface markers expressed on MSC have been proposed as useful tools for the isolation of MSC from other cell populations. However, the correlation between the expression of MSC markers and the ability to support tissue regeneration in vivo has not been well examined.

Hypoxia responsive mesenchymal stem cells derived from human umbilical cord blood are effective for bone repair.

Mesenchymal stem cells (MSCs) are highly useful in a variety of cell therapies owing to their multipotential differentiation capability. MSCs derived from umbilical cord blood are generally isolated by their plastic adherence without using specific cell surface markers and examined for their osteogenic, adipogenic, and chondrogenic differentiation properties retrospectively. Here, we report 2 subpopulations of MSCs, separated based on aldehyde dehydrogenase (ALDH) activity.

Hypoxia-inducible transcription factor-2alpha in endothelial cells regulates tumor neovascularization through activation of ephrin A1.

The hypoxia-inducible transcription factors (HIF)-1alpha and -2alpha mediate responses to hypoxia, such as tumor neovascularization. To determine the function of HIF-2alpha in vascular endothelial cells (ECs), we examined vascular formation in HIF-2alpha knockdown (kd/kd) mice transplanted with tumors. We observed that both the tumor size and the number of large vessels growing within transplanted melanomas were significantly reduced in kd/kd recipients compared with wild-type (WT) mice.

Reduced BMP4 abundance in Gata2 hypomorphic mutant mice result in uropathies resembling human CAKUT.

Constitutive loss of transcription factor GATA-2 leads to embryonic lethality from primitive erythropoietic failure. We serendipitously discovered an essential contribution of GATA-2 to urogenital development when the hematopoietic deficiency of Gata2 null mutant animals was complemented by a Gata2 yeast artificial chromosome (YAC) transgene; these mice died from a perinatal lethal urogenital abnormality. Here, we report the generation and analysis of Gata2 hypomorphic mutant (Gata2(fGN)/(/fGN)) mice, which suffered from hydronephrosis and megaureter, as do the YAC-rescued Gata2 null mutants.

Abnormal heart development and lung remodeling in mice lacking the hypoxia-inducible factor-related basic helix-loop-helix PAS protein NEPAS.

Hypoxia-inducible factors (HIFs) are crucial for oxygen homeostasis during both embryonic development and postnatal life. Here we show that a novel HIF family basic helix-loop-helix (bHLH) PAS (Per-Arnt-Sim) protein, which is expressed predominantly during embryonic and neonatal stages and thereby designated NEPAS (neonatal and embryonic PAS), acts as a negative regulator of HIF-mediated gene expression. NEPAS mRNA is derived from the HIF-3alpha gene by alternative splicing, replacing the first exon of HIF-3alpha with that of inhibitory PAS.

Role of hypoxia-inducible factor-2alpha in endothelial development and hematopoiesis.

Endothelial cells (EC) are important components for vessel formation and hematopoiesis. The proliferation and differentiation of EC are performed under the close influence of hypoxia-inducible factors (HIFs), which are master transcription factors that regulate vasculogenesis and angiogenesis in response to hypoxic stimuli. During early development of embryos, EC are directly involved in hematopoiesis and are known to act as stromal cells, which generate a variety of regulatory factors, including cytokines and growth factors, and maintain adhesive interactions with the hematopoietic cells essential for their survival and function in the microenvironment.

Identification of functional endothelial progenitor cells suitable for the treatment of ischemic tissue using human umbilical cord blood.

Umbilical cord blood (UCB) has been used as a potential source of various kinds of stem cells, including hematopoietic stem cells, mesenchymal stem cells, and endothelial progenitor cells (EPCs), for a variety of cell therapies. Recently, EPCs were introduced for restoring vascularization in ischemic tissues. An appropriate procedure for isolating EPCs from UCB is a key issue for improving therapeutic efficacy and eliminating the unexpected expansion of nonessential cells.

Transgene insertion in proximity to the c-myb gene disrupts erythroid-megakaryocytic lineage bifurcation.

The nuclear proto-oncogene c-myb plays crucial roles in the growth, survival, and differentiation of hematopoietic cells. We established three lines of erythropoietin receptor-transgenic mice and found that one of them exhibited anemia, thrombocythemia, and splenomegaly. These abnormalities were independent of the function of the transgenic erythropoietin receptor and were observed exclusively in mice harboring the transgene homozygously, suggesting transgenic disruption of a certain gene.

Graded levels of GATA-1 expression modulate survival, proliferation, and differentiation of erythroid progenitors.

Transcription factor GATA-1 plays an important role in gene regulation during the development of erythroid cells. Several reports suggest that GATA-1 plays multiple roles in survival, proliferation, and differentiation of erythroid cells. However, little is known about the relationship between the level of GATA-1 expression and its nature of multifunction to affect erythroid cell fate.

Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome.

Transient myeloproliferative disorder (TMD) is a leukemoid reaction occurring occasionally in Down syndrome newborn infants. Acute megakaryocytic leukemia (AMKL) develops in approximately 20% to 30% of the cases with TMD. Recently, acquired mutations in the N-terminal activation domain of the GATA-1 gene, encoding the erythroid/megakaryocytic transcription factor GATA-1, have been reported in Down syndrome-related AMKL (DS-AMKL).