Deficiency of the microRNA-31-microRNA-720 pathway in the plasma and endothelial progenitor cells from patients with coronary artery disease.

OBJECTIVE: Defects in angiogenesis/vasculogenesis or vessel repair are major complications of coronary artery disease (CAD). Endothelial progenitor cells (EPCs) play a fundamental role in postnatal vascular repair and CAD. The role of microRNAs in CAD pathogenesis and their potential as biomarkers remain to be elucidated. APPROACH AND RESULTS: MicroRNA-31 (miR-31) level in both the plasma and EPCs of patients with CAD is found lower. miR-31 regulates EPC activities by targeting FAT atypical cadherin 4 and thromboxane A2 receptor, which show increased expression in CAD EPCs. Overexpressing miR-31 in CAD EPCs rescued their angiogenic and vasculogenic abilities both in vitro and in vivo. When exploring approaches to restore endogenous miR-31, we found that far-infrared treatment enhanced the expression of not only miR-31, but also miR-720 in CAD EPCs. miR-720, which was also decreased in EPCs and the plasma of patients with CAD, stimulated EPC activity by targeting vasohibin 1. The miR720-vasohibin 1 pair was shown to be downstream of FAT atypical cadherin 4, but not of thromboxane A2 receptor. FAT atypical cadherin 4 inhibited miR-720 expression via repression of the planar cell polarity signaling gene four-jointed box 1 (FJX1), which was required for miR-720 expression through a hypoxia-inducible factor 1, α subunit-dependent mechanism. Restoring miR-720 level strengthened activity of CAD EPCs. The miR-31-miR-720 pathway is shown critical to EPC activation and that downregulation of this pathway contributes to CAD pathogenesis. Circulating levels of miR-31, miR-720, and vasohibin 1 have the potential to allow early diagnosis of CAD and to act as prognosis biomarkers for CAD and other EPC-related diseases. CONCLUSIONS: Manipulating the expression of the miR-31-miR-720 pathway in malfunction EPCs should help develop novel therapeutic modalities.

Genetic module and miRNome trait analyses reflect the distinct biological features of endothelial progenitor cells from different anatomic locations.

BACKGROUND: Endothelial progenitor cells (EPCs) play a fundamental role in post-natal vascular repair, yet EPCs from different anatomic locations possess unique biological properties. The underlying mechanisms are unclear. RESULTS: EPCs from CB expressed abundant genes involved in cell cycle, hypoxia signalling and blood vessel development, correlating with the phenotypes that CB-EPCs proliferated more rapidly, migrated faster, and formed tubule structure more efficiently. smRNA-seq further deciphered miRNome patterns in EPCs isolated from CB or PB: 54 miRNAs were enriched in CB-EPCs, while another 50 in PB-EPCs. Specifically, CB-EPCs expressed more angiogenic miRNAs such as miR-31, while PB-EPCs possessed more tumor suppressive miRNAs including miR-10a. Knocking down miR-31 levels in CB-EPCs suppressed cell migration and microtubule formation, while overexpressing miR-31 in PB-EPCs helped to recapitulate some of CB-EPC functions. CONCLUSIONS: Our results show the foundation for a more detailed understanding of EPCs from different anatomic sources. Stimulating the expression of angiogenic microRNAs or genes in EPCs of low activity (such as those from patients with cardiovascular diseases) might allow the development of novel therapeutic strategies.

Comparative transcriptome analysis reveals a fetal origin for mesenchymal stem cells and novel fetal surface antigens for noninvasive prenatal diagnosis.

OBJECTIVE: Mesenchymal stem cells (MSCs) are an attractive source for providing the cells necessary for regenerating damaged tissues. Fetal MSCs (fMSCs) are known to proliferate fast and have an excellent osteogenic capacity, yet the underlying mechanisms need to be explored. A better understanding of MSCs from different anatomic origins and ages will eventually benefit cell-based therapies, as well as subsequent mechanistic studies in the field of stem cell biology. MATERIALS AND METHODS: We identified the molecular signatures of fetal and adult MSCs via a meta-analytic strategy and compared the enriched canonical pathways and genetic networks within each signature. RESULTS: Fetal MSCs were found to express more cell cycle genes, which is consistent with the results of wetlab functional assays. In addition, the genes involved in vasculogenesis, neurogenesis, Wnt, MAPKKK pathways, and RNA splicing were found to be enriched in fMSCs. Correlating with the overexpression of multilineage differentiation genes, fMSCs share more genes with embryonic stem cells (ESCs) and are, therefore, more primitive. Further exploration into the transcriptome similarities revealed that MSCs from umbilical cord blood (UCB) express dominant fMSC genes, but not adult genes, suggesting a fetal origin for UCB MSCs. Novel surface proteins that were dominantly expressed in fetal and UCB MSCs, but not in adult MSCs or maternal PBMCs, were also identified. CONCLUSION: Our results systematically revealed the underlying genes and regulatory networks of two MSCs from unique origins, the resulting phenotypes, as well as the origin of UCB MSCs. The novel membrane proteins on the fetal MSC surface are promising candidate biomarkers for positively isolating fetal MSCs from maternal blood for noninvasive prenatal diagnosis.

Deciphering the neuroprotective mechanisms of Bu-yang Huan-wu decoction by an integrative neurofunctional and genomic approach in ischemic stroke mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Bu-yang Huan-wu decoction (BHD) is a famous traditional Chinese medicine formula that has been used clinically in Asia to treat stroke-induced disability for centuries, but the underlying neuroprotective mechanisms are not fully understood. AIM OF THE STUDY: In this study, we aim to investigate the mechanisms of action using an integrative neurofunctional and broad genomics approach. MATERIALS AND METHODS: Male ICR mice were subjected to an acute ischemic stroke by inducing a middle cerebral ischemic/reperfusion (CI/R) injury. To examine whether BHD could extend the lifespan of mice with a stroke, we used oral administration of BHD (0.5 and 1.0g/kg) twice daily starting from 2h after ischemia and compared this with vehicle control treatments, recombinant tissue-type plasminogen activator (rt-PA, 10mg/kg, i.v.), and MK-801 (0.2mg/kg, i.p.). An integrative neurofunctional and genomic approach was performed to elucidate the underlying molecular mechanisms of BHD. RESULTS: More than 80% of the mice died within 2 days after stroke induction in the vehicle control treatment group. However, the survival rates and life-spans of mice treated with BHD, rt-PA and MK-801 were significantly enhanced as compared to the vehicle-treated CI/R group in all three cases. Mice treated with BHD (1.0g/kg) showed the greatest protective effect across all groups. BHD successfully restored brain function, ameliorated the cerebral infarction, and significantly improved the neurological deficits of the mice with a stroke. BHD also reduced inflammation, oxidative stress, and apoptosis, as well as improved neurogenesis. The molecular impacts of BHD were assessed by genome-wide transcriptome analysis using brains from the CI/R mice. The results showed a total of 377 ischemia-induced probe-sets that were significantly influenced by BHD including 93 probe-sets that were commonly more abundant in BHD-treated and sham mice, and another 284 ischemia-induced probe sets that were suppressed by BHD. Mining the functional modules and genetic networks of these 377 genes revealed a significant upregulation of neuroprotective genes associated with neurogenesis (6 genes) and nervous system development (9 genes), and a significant down-regulation of destructive genes associated with the induction of inflammation (14 genes), apoptosis (15 genes), angiogenesis (11 genes) and blood coagulation (7 genes) by BHD. CONCLUSIONS: Our results suggested that BHD is able to protect mice against stroke and extend lifespan primarily through a significant down-regulation of genes involved in inflammation, apoptosis, angiogenesis and blood coagulation, as well as an up-regulation of genes mediating neurogenesis and nervous system development. The changes in expression after treatment with BHD are beneficial after ischemic stroke.