Cell Research (2016) 26:1071-1072. © 2016 IBCB, SIBS, CAS All rights reserved 1001-0602/16 $ 32.00 RESEARCH HIGHLIGHT www.nature.com/cr Vascular Procr+ stem cells: Finding new branches while looking for the roots Cell Research (2016) 26:1071-1072. doi:10.1038/cr.2016.91; published online 2 August 2016 Generation and growth of the cells are the major source of mature Procr+ endothelial cells in vivo, Yu et blood vasculature network is a highly endothelial cells for vascular renewal al. elegantly carried out lineage trac- synchronized process, requiring coor- and repair, over bone marrow-derived ing experiments, revealing that Procr+ dinated efforts of endothelial cells and endothelial precursors [1]. The report endothelial cells not only significantly pericytes to maintain blood vessel in- by Yu et al. [2] provides strong evidence contribute to adult neovascularization, tegrity and regeneration. In a recent to support this concept and identifies but unexpectedly, are bipotent stem cells paper published in Cell Research, Yu protein C receptor-expressing (Procr, which can also give rise to pericytes in et al. identified and characterized also known as endothelial protein C normal development and homeostasis. bipotent Procr-expressing vascular receptor — EPCR) endothelial stem To the best of our knowledge and under- endothelial stem cells, which give rise cells as the apex of the bipotent lineage standing, this is the first documentation to both endothelial cells and pericytes. tree for both endothelial cells and peri- of an adult bipotent common vascular The vasculature is a complex trans- cytes, providing new understanding on progenitor that gives rise to both endo- port system, composed of a remarkable the root of adult neovascularization in thelial and periendothelial cells. These network of arteries, veins and connect- homeostasis and injury repair. results are in line with previous obser- ing capillaries of the blood system that To identify vascular endothelial stem vations revealing a common bipotent supply every organ with oxygen and cells (VESCs), Yu and colleagues took embryonic vascular progenitor cell that nutrients. Blood vessels also regulate advantage of the mammary gland which differentiates into both endothelial and organ development, regeneration and develops mostly in the postnatal stage. smooth muscle cells [3]. stem cell behavior. Endothelial stem The authors demonstrate that Procr- Procr has been identified as a stem cells are highly plastic and can rapidly expressing endothelial stem cells exhibit cell marker also in various other tis- switch from long-term quiescence to ac- robust in vitro clonogenic potential and sues including long-term repopulating tive angiogenic growth upon metabolic that their stemness capacities can be hematopoietic stem cells (LT-HSCs) in and stress stimulations. Vascular growth retained in culture. Importantly, when the fetal liver during embryo develop- and remodeling are vital for successful transplanted into an empty fat pad of ment [4] and adult bone marrow [5, 6], organ growth and play a major role in pubertal recipients, Procr-expressing and more recently in mammary stem tissue repair. However, this dynamic endothelial stem cells could functionally cells [7]. Procr has clear endothelial property also holds dark sides as vas- incorporate into an existing vessel and characteristics, and its ligation with cular sprouting provides survival and form new vessels in the mammary fat the serine protease, activated protein C growth cues to allow tumor progression pads, demonstrating robust regenerative (aPC), induces classic PAR1-mediated and metastasis spreading. Identifying capacity of Procr+ VESCs. The authors anticoagulation with anti-apoptotic and the root origin of the vascular segments extend their observations and show that anti-inflammatory activities, as well as could potentially make it possible to aid Procr is a common marker for VESCs promotes endothelial barrier protection in the development of therapies to pro- in the vasculature of other adult tissues, and stabilization [8]. Current evidence mote vascular repair or to prevent blood including the skin and retina. Targeted reveals that the aPC/EPCR pathway vessel growth within tumors. During ablation of Procr-expressing endothelial plays an important role in both fetal the last decade, much effort has been cells revealed the functional importance hematopoietic stem cell survival [4] devoted toward isolating and character- of Procr+ VESCs for blood vessel devel- and adult LT-HSC retention in the bone izing the adult stem cells that give rise opment and regeneration during normal marrow and protection from myelo- to the vascular endothelium. A growing retinal development and in vascular res- toxic insult [9]. Protection from DNA body of evidence indicates that tissue- toration upon hind limb ischemic injury. damaging agents via aPC/EPCR/PAR1 resident endothelial stem and progenitor To further verify the clonogenicity of signaling limits nitric oxide generation www.cell-research.com | Cell Research | SPRINGER NATURE 1072 and Cdc42 activity, leading to enhanced mary stem cell population [7], but is also pericyte cell population? Whether VLA4-mediated adhesion and stem cell highly expressed by a cancer stem cell- resident Procr+ stem cell pool becomes retention to ensure preservation of the like populations in aggressive human exhausted in disease states, aging and bone marrow stem cell pool [9]. Pres- breast cancer cells [12]. Since cancer- upon vascular injury remains to be ervation of Procr expression among dif- initiating cells are the lineage tree origin determined. Differences in the gene ferent stem cell types strongly implies for chemotherapy resistance and disease expression profile of Procr+ VESCs that Procr provides common stem cell relapse, a better understanding of how a versus hematopoietic and mammary signals, which may preserve the ‘stem- single Procr+ stem cell remains dormant stem cells may contribute to our global ness’ phenotype (Figure 1). within its niches and how it is protected understanding on ‘stemness’ identity The cancer stem cell paradigm refers will broaden our knowledge of how to and to further determination of their to the ability of cancer cell subpopula- eliminate the hiding cancer stem cell. phenotypic properties. The study by Yu tion to initiate tumorigenesis by under- In light of these important observa- et al. may also have therapeutic impli- going extensive self-renewal and dif- tions, the study by Yu et al. [2] opens cations as neovascularization holds the ferentiation [10]. It becomes clear that up new horizons, but raises questions key to wound healing, and angiogenesis the high frequency of relapse predicts at the same time. Based on the bipotent is a target for antitumor treatments. For that cancer stem cells are resistant to potential of Procr+ endothelial cells, example, does induction of Procr by standard therapy [11], therefore making what is the mechanism that triggers Wnt signaling [7] or activation by its strong claim that targeting the stem cell the endothelial regeneration process ligand aPC initiate vascular growth? population will likely lead to improved of Procr-expressing stem cells? What On the other hand, could targeting Procr patient outcomes. Procr was identified are the signals that enable coordinate by neutralizing antibodies be beneficial as a marker not only for healthy mam- differentiation to both endothelial and in fighting cancer? Finding an answer to those potentially clinically-relevant questions might yield an exciting find- ing and a rewarding journey. Shiri Gur-Cohen1, Tsvee Lapidot1 1Weizmann Institute of Science, Immunology Department, Rehovot, Israel Correspondence: Tsvee Lapidot E-mail: [email protected] References 1 Rinkevich Y, Lindau P, Ueno H, et al. Na- ture 2011; 476:409-413. 2 Yu QC, Song W, Wang D, et al. Cell Res 2016; 26:1079-1098. 3 Yamashita J, Itoh H, Hirashima M, et al. Na- ture 2000; 408:92-96. 4 Iwasaki H, Arai F, Kubota Y, et al. Blood 2010; 116:544-553. 5 Kent DG, Copley MR, Benz C, et al. Blood 2009; 113:6342-6350. 6 Balazs AB, Fabian AJ, Esmon CT, et al. Blood 2006; 107:2317-2321. 7 Wang D, Cai C, Dong X, et al. Nature 2015; 517:81-84. 8 Esmon CT. Semin Immunopathol 2012; 34:127-132. Figure 1 Procr is widely expressed by stem cells in various tissues. (A) Procr is 9 Gur-Cohen S, Itkin T, Chakrabarty S, et al. expressed by vascular endothelial stem cells (VESCs). Procr+ VESCs are bipotent, Nat Med 2015; 21:1307-1317. giving rise to endothelial cells and pericytes. (B) Procr is expressed by mammary 10 Lapidot T, Sirard C, Vormoor J, et al. Nature stem cells (MaSCs), and can be differentiated into all lineages of the mammary epi- 1994; 367:645-648. thelium including basal and luminal cells. (C) Procr (EPCR) is highly expressed by 11 Ding L, Ley TJ, Larson DE, et al. Nature bone marrow hematopoietic stem cells (HSCs) located in a thrombomodulin- and 2012; 481:506-510. aPC-enriched arterial microenvironment. EPCR signaling, manifested by aPC liga- 12 Schaffner F, Yokota N, Carneiro-Lobo T, et tion, promotes stem cell retention in the bone marrow and protection from cytotoxic al. PLoS One 2013; 8:e61071. damage. SPRINGER NATURE | Cell Research | Vol 26 No 10 | October 2016.