Identification of blood vascular endothelial stem cells by the expression of protein C receptor

Yu, Qing; Song, Wenqian; Wang, Daisong; Zeng, Yi Arial

doi:10.1038/cr.2016.85

Cited by 122 publications

(134 citation statements)

References 57 publications

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“…Thus, this study provided strong evidence for the contribution of Sca1 + ‐VPCs to vascular injury repair and angiogenesis in ischemic tissues. Using different cell surface markers, different groups have identified different types of vessel wall‐resident stem/progenitor cells that contribute to neo‐angiogenesis . In this study, we have demonstrated that 7A was essential for neo‐angiogenesis in response to vascular injury.…”

Section: Discussionmentioning

confidence: 67%

A histone deacetylase 7-derived peptide promotes vascular regeneration via facilitating 14-3-3γ phosphorylation

Yang

Moraga

et al. 2020

Stem Cells

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Histone deacetylase 7 (HDAC7) plays a pivotal role in the maintenance of the endothelium integrity. In this study, we demonstrated that the intron‐containing Hdac7 mRNA existed in the cytosol and that ribosomes bound to a short open reading frame (sORF) within the 5′‐terminal noncoding area of this Hdac7 mRNA in response to vascular endothelial growth factor (VEGF) stimulation in the isolated stem cell antigen‐1 positive (Sca1+) vascular progenitor cells (VPCs). A 7‐amino acid (7A) peptide has been demonstrated to be translated from the sORF in Sca1+‐VPCs in vitro and in vivo. The 7A peptide was shown to receive phosphate group from the activated mitogen‐activated protein kinase MEKK1 and transfer it to 14‐3‐3 gamma protein, forming an MEKK1‐7A‐14‐3‐3γ signal pathway downstream VEGF. The exogenous synthetic 7A peptide could increase Sca1+‐VPCs cell migration, re‐endothelialization in the femoral artery injury, and angiogenesis in hind limb ischemia. A Hd7‐7sFLAG transgenic mice line was generated as the loss‐of‐function model, in which the 7A peptide was replaced by a FLAG‐tagged scrabbled peptide. Loss of the endogenous 7A impaired Sca1+‐VPCs cell migration, re‐endothelialization of the injured femoral artery, and angiogenesis in ischemic tissues, which could be partially rescued by the addition of the exogenous 7A/7Ap peptide. This study provides evidence that sORFs can be alternatively translated and the derived peptides may play an important role in physiological processes including vascular remodeling.

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Section: Discussionmentioning

confidence: 67%

A histone deacetylase 7-derived peptide promotes vascular regeneration via facilitating 14-3-3γ phosphorylation

Yang

Moraga

et al. 2020

Stem Cells

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“…New endothelium in physiologic angiogenesis is thought to arise principally from local EC 67 , and circulating endothelial progenitors do not contribute to new endothelium in immunized LN 4 . Prior studies have highlighted multipotent vessel-resident EC progenitor populations in large vessels 68,69 and lung 70 and precursors in developing bone 71 that can differentiate into diverse EC phenotypes. CRP appear distinct from these populations: They lack Bst1 and Procr , markers of resident endothelial progenitors described in large vessels of liver 68 and fat pad 69 .…”

Section: Discussionmentioning

confidence: 99%

A molecular map of lymph node blood vascular endothelium at single cell resolution

Brulois

Rajaraman

Szade

et al. 2020

Preprint

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48 49 Blood vascular endothelial cells (BECs) control the immune response by regulating immune 50 cell recruitment, metabolite exchange and blood flow in lymphoid tissues. However, the 51 diversity of BEC and their origins during immune angiogenesis remain poorly understood. 52Here we profile transcriptomes of BEC from mouse peripheral lymph nodes and map key 53 phenotypes to the vasculature. Our analysis identifies multiple novel subsets including a 54 venous population whose gene signature predicts an unexpectedly selective role in myeloid 55 cell (vs lymphocyte) recruitment to the medulla, confirmed by 2 photon videomicroscopy. 56We define five phenotypes of capillary lining BEC including a capillary resident regenerative 57 population (CRP) that displays stem cell and migratory gene signatures and contributes to58 homeostatic BEC turnover and to vascular neogenesis after immunization. Trajectory 59 analyses reveal retention of developmental programs along a progression of cellular 60 phenotypes from CRP to mature venous and arterial BEC subsets. Overall, our single cell 61 atlas provides a molecular blueprint of the lymph node blood vasculature and defines subset 62 specialization for immune cell recruitment and vascular homeostasis. 63 64 Introduction 65The vascular endothelium lining blood vessels regulates exchange of oxygen and 66 metabolites between the blood vascular compartment and tissues. In lymph nodes (LN), 67 additionally, the endothelium plays essential roles in controlling immune cell access. The 68 organization of the vasculature in LN is well characterized: Arteries entering at the hilus lead to 69 capillary arcades in the LN cortex; capillaries link to 'high endothelial venules' (HEV), the post 70 capillary venules that recruit lymphocytes from the blood 1 ; and the vasculature exits the lymph 71 node at the hilus. Upon immune challenge, lymph nodes increase in volume up to 10-fold or more 72 within days, and the vascular endothelium expands roughly proportionally from local precursors 1,2 . 73Vessel expansion involves extensive proliferation of both capillary and high endothelial cells 74 (HEC) 3 , without contribution from blood borne progenitors 4 ; and an increase in vessel numbers 75 through intussusceptive (splitting) angiogenesis 5 . However, the nature and extent of endothelial 76 cell diversity within LN remains incompletely understood. 77Single cell RNA profiling is a transformative technology for the identification of cell 78 diversity and elucidation of developmental and physical relationships. Here we provide a survey 79 of blood vessel endothelial cells (BEC) from mouse peripheral lymph nodes (PLN). We confirm 80 known features of high endothelium 6,7 , identify novel endothelial subsets, uncover unexpected 81 diversity among capillary cells and demonstrate a distinctive role of medullary veins in selective 82 myeloid cell recruitment. We define gene signatures and transcription regulatory factors for these 83 subsets, and map key subsets to the vasculature. We also identify a p...

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“…Mice carrying a variant of EPCR with impaired ability to bind PC/aPC are viable without reported placental thrombosis and intrauterine death 17 . Though most well studied for their role in anticoagulation, new roles of aPC and EPCR in stem cell function [18][19][20][21][22] , inflammation [23][24][25] and immunity 26,27 have recently emerged. Thus, the mechanism of placental failure and whether it is primarily mediated by the loss of anticoagulation by EPCR remains unclear.…”

Section: Introductionmentioning

confidence: 99%

The Endothelial Protein C Receptor plays an essential role in the maintenance of Pregnancy

Castillo

Yang

Sigala

et al. 2020

Preprint

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Placenta-mediated pregnancy complications are a major challenge in the management of maternal-fetal health. Maternal thrombophilia is a suspected risk factor but the role of thrombotic processes in these complications and the potential for antithrombotic treatment have remained unclear. Endothelial Protein C Receptor (EPCR) is an anticoagulant protein highly expressed in the placenta. EPCR autoantibodies and specific gene variants of EPCR are associated with poor pregnancy outcomes. In mice, fetal EPCR deficiency results in placental failure and in utero death. Adult EPCR-deficient mice generated by maintaining placental expression exhibit plasma markers of thrombophilia without overt thrombosis. We demonstrate that inactivation of clotting factor VIII or Protease Activated Receptor 4 (Par4), Par3 or integrin αIIb in the mother allows placental development and intrauterine survival of murine embryos lacking EPCR. Rescued EPCR-deficient embryos exhibit thrombosis in placental venous sinuses at late gestation and a high rate of neonatal lethality. In contrast to fetal EPCR deficiency, maternal deficiency of EPCR results in frequent stillbirths and maternal death accompanied by pathological findings that resemble placental abruption and consumptive coagulopathy. Inactivation of Par4, but not clotting factor VIII, prevents maternal death and restores normal pregnancy outcomes. These observations establish a cause-effect relationship between maternal thrombophilia and placental abruption. They demonstrate that sites of uteroplacental thrombosis and the potential response to antithrombotic intervention may differ with gestational age and maternal versus fetal origin of thrombophilia. Our findings highlight the potential for therapeutic inhibition of thrombin-mediated platelet activation in a subset of pregnancy complications.KEY POINTSMurine model establishes a cause-effect relationship between maternal thrombophilia, retroplacental hemorrhage and severe pregnancy complications.Thrombin-mediated activation of maternal platelets is a key event in thrombophilia-associated pregnancy complications and a potential target of therapeutic intervention.Maternal venous channels in uteroplacental circulation are additional sites of thrombotic pathology associated with adverse neonatal outcomes.

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Identification of blood vascular endothelial stem cells by the expression of protein C receptor

Cited by 122 publications

References 57 publications

A histone deacetylase 7-derived peptide promotes vascular regeneration via facilitating 14-3-3γ phosphorylation

A histone deacetylase 7-derived peptide promotes vascular regeneration via facilitating 14-3-3γ phosphorylation

A molecular map of lymph node blood vascular endothelium at single cell resolution

The Endothelial Protein C Receptor plays an essential role in the maintenance of Pregnancy

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