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Hemogenic endothelium

Dionna M Kasper, Stefania Nicoli
Purpose of the Review: Blood specification is a highly dynamic process, whereby committed hemogenic endothelial cells (ECs) progressively transdifferentiate into multipotent, self-renewing hematopoietic stem cells (HSCs). Massive changes in gene expression must occur to switch cell identity, however the factors that mediate such an effect were a mystery until recently. This review summarizes the higher-order mechanisms involved in endothelial to hematopoietic reprogramming identified thus far...
March 2018: Current Stem Cell Reports
Yekaterina Galat, Irina Elcheva, Svetlana Dambaeva, Dimantha Katukurundage, Kenneth Beaman, Philip M Iannaccone, Vasiliy Galat
Improving the understanding of the intricacies of hematopoietic specification of induced or embryonic pluripotent stem cells is beneficial for many areas of research and translational medicine. Currently, it is not clear whether during hPSC hematopoietic differentiation in vitro the maturation of definitive progenitors proceeds through a primitive progenitor (hemangioblast) intermediate or develops independently. The objective of this study is to investigate the early stages of hematopoietic specification of pluripotent stem cells in vitro...
June 4, 2018: Experimental Hematology
HyunJun Kang, Walatta-Tseyon Mesquitta, Ho Sun Jung, Oleg V Moskvin, James A Thomson, Igor I Slukvin
The transcriptional factor GATA2 is required for blood and hematopoietic stem cell formation during the hemogenic endothelium (HE) stage of development in the embryo. However, it is unclear if GATA2 controls HE lineage specification or if it solely regulates endothelial-to-hematopoietic transition (EHT). To address this problem, we innovated a unique system, which involved generating GATA2 knockout human embryonic stem cell (hESC) lines with conditional GATA2 expression (iG2-/- hESCs). We demonstrated that GATA2 activity is not required for VE-cadherin+ CD43- CD73+ non-HE or VE-cadherin+ CD43- CD73- HE generation and subsequent HE diversification into DLL4+ arterial and DLL4- non-arterial lineages...
May 24, 2018: Stem Cell Reports
Mi Ae Park, Akhilesh Kumar, Ho Sun Jung, Gene Uenishi, Oleg V Moskvin, James A Thomson, Igor I Slukvin
Understanding the pathways guiding the development of definitive hematopoiesis with lymphoid potential is essential for advancing human pluripotent stem cell (hPSC) technologies for the treatment of blood diseases and immunotherapies. In the embryo, lymphoid progenitors and hematopoietic stem cells (HSCs) arise from hemogenic endothelium (HE) lining arteries but not veins. Here, we show that activation of the arterial program through ETS1 overexpression or by modulating MAPK/ERK signaling pathways at the mesodermal stage of development dramatically enhanced the formation of arterial-type HE expressing DLL4 and CXCR4...
May 22, 2018: Cell Reports
Christopher B Mahony, Corentin Pasche, Julien Y Bertrand
Understanding the molecular pathways controlling hematopoietic stem cell specification and expansion is a necessary milestone to perform regenerative medicine. Here, we used the zebrafish model to study the role of the ckit signaling pathway in this process. We show the importance of kitb/kitlgb signaling in the specification and expansion of hematopoietic stem cells (HSCs), in the hemogenic endothelium and caudal hematopoietic tissue (CHT), respectively. Moreover, we identified the zebrafish ortholog of Oncostatin M (osm) in the zebrafish genome...
May 10, 2018: Stem Cell Reports
Gene I Uenishi, Ho Sun Jung, Akhilesh Kumar, Mi Ae Park, Brandon K Hadland, Ethan McLeod, Matthew Raymond, Oleg Moskvin, Catherine E Zimmerman, Derek J Theisen, Scott Swanson, Owen J Tamplin, Leonard I Zon, James A Thomson, Irwin D Bernstein, Igor I Slukvin
NOTCH signaling is required for the arterial specification and formation of hematopoietic stem cells (HSCs) and lympho-myeloid progenitors in the embryonic aorta-gonad-mesonephros region and extraembryonic vasculature from a distinct lineage of vascular endothelial cells with hemogenic potential. However, the role of NOTCH signaling in hemogenic endothelium (HE) specification from human pluripotent stem cell (hPSC) has not been studied. Here, using a chemically defined hPSC differentiation system combined with the use of DLL1-Fc and DAPT to manipulate NOTCH, we discover that NOTCH activation in hPSC-derived immature HE progenitors leads to formation of CD144+ CD43- CD73- DLL4+ Runx1 + 23-GFP+ arterial-type HE, which requires NOTCH signaling to undergo endothelial-to-hematopoietic transition and produce definitive lympho-myeloid and erythroid cells...
May 8, 2018: Nature Communications
Lucy Sulzberger, Elysia M S Tan, Paul F Davis, Helen D Brasch, Swee T Tan, Tinte Itinteang
We have recently demonstrated the expression of embryonic stem cell markers on the endothelium of infantile hemangioma, a functional hemogenic endothelium with the capacity for primitive erythropoiesis in vitro . Despite recent work characterizing stem cells within proliferating infantile hemangioma, the expression of STAT proteins, well documented for their roles in stem cell signaling, has not been investigated. 3,3-Diaminobenzidine and immunofluorescence immunohistochemical staining revealed expression of pSTAT1, pSTAT3 and pSTAT5 in proliferating infantile hemangioma samples with the strongest expression of pSTAT3...
2018: Frontiers in Surgery
Xiaoping Han, Haide Chen, Daosheng Huang, Huidong Chen, Lijiang Fei, Chen Cheng, He Huang, Guo-Cheng Yuan, Guoji Guo
BACKGROUND: Human pluripotent stem cells (hPSCs) provide powerful models for studying cellular differentiations and unlimited sources of cells for regenerative medicine. However, a comprehensive single-cell level differentiation roadmap for hPSCs has not been achieved. RESULTS: We use high throughput single-cell RNA-sequencing (scRNA-seq), based on optimized microfluidic circuits, to profile early differentiation lineages in the human embryoid body system. We present a cellular-state landscape for hPSC early differentiation that covers multiple cellular lineages, including neural, muscle, endothelial, stromal, liver, and epithelial cells...
April 5, 2018: Genome Biology
Hiroki Nagai, Masahiro Shin, Wei Weng, Fumie Nakazawa, Lars Martin Jakt, Cantas Alev, Guojun Sheng
The field of hematopoietic and vascular developmental research owes its origin to the chick embryo. Many key concepts, such as the hematopoietic stem cell, hemangioblast and hemogenic endothelium, were first proposed in this model organism. Genetically tractable models have gradually replaced the chick in the past two decades. However, advances in comparative genomics, transcriptomics and promoteromics promise a re-emergence of the chick embryo as a powerful model for hematopoietic/vascular research. This review summarizes the current status of our understanding of early blood/vascular development in the chick, focusing primarily on the processes of primitive hematopoiesis and early vascular network formation in the extraembryonic and lateral plate mesoderm territories...
2018: International Journal of Developmental Biology
Ewa Jankowska-Steifer, Justyna Niderla-Bielińska, Bogdan Ciszek, Marek Kujawa, Mateusz Bartkowiak, Aleksandra Flaht-Zabost, Daria Klosinska, Anna Ratajska
During embryonic development, hematopoietic cells are present in areas of blood-vessel differentiation. These hematopoietic cells emerge from a specific subpopulation of endothelial cells called the hemogenic endothelium. We have previously found that mouse proepicardium contained its own population of endothelial cells forming a network of vascular tubules. We hypothesize that this EC population contains cells of hematopoietic potential. Therefore, we investigated an in vitro hematopoietic potential of proepicardial cell populations...
March 16, 2018: Histochemistry and Cell Biology
Michael Lie-A-Ling, Elli Marinopoulou, Andrew J Lilly, Mairi Challinor, Rahima Patel, Christophe Lancrin, Valerie Kouskoff, Georges Lacaud
During ontogeny, hematopoietic stem and progenitor cells arise from hemogenic endothelium through an endothelial-to-hematopoietic transition that is strictly dependent on the transcription factor RUNX1. Although it is well established that RUNX1 is essential for the onset of hematopoiesis, little is known about the role of RUNX1 dosage specifically in hemogenic endothelium and during the endothelial-to-hematopoietic transition. Here, we used the mouse embryonic stem cell differentiation system to determine if and how RUNX1 dosage affects hemogenic endothelium differentiation...
March 12, 2018: Development
Saloomeh Mokhtari, Evan Colletti, Weihong Yin, Chad Sanada, Zanetta Lamar, Paul J Simmons, Steven Walker, Colin Bishop, Anthony Atala, Esmail D Zanjani, Christopher D Porada, Graça Almeida-Porada
The presence, within the human bone marrow, of cells with both endothelial and hemogenic potential has been controversial. Herein, we identify, within the human fetal bone marrow, prior to establishment of hematopoiesis, a unique APLNR+, Stro-1+ cell population, co-expressing markers of early mesodermal precursors and/or hemogenic endothelium. In adult marrow, cells expressing similar markers are also found, but at very low frequency. These adult-derived cells can be extensively culture expanded in vitro without loss of potential, they preserve a biased hemogenic transcriptional profile, and, upon in vitro induction with OCT4, assume a hematopoietic phenotype...
February 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Nadine Teichweyde, Lara Kasperidus, Sebastian Carotta, Valerie Kouskoff, Georges Lacaud, Peter A Horn, Stefan Heinrichs, Hannes Klump
Generation of hematopoietic stem cells (HSCs) from pluripotent stem cells, in vitro, holds great promise for regenerative therapies. Primarily, this has been achieved in mouse cells by overexpression of the homeotic selector protein HOXB4. The exact cellular stage at which HOXB4 promotes hematopoietic development, in vitro, is not yet known. However, its identification is a prerequisite to unambiguously identify the molecular circuits controlling hematopoiesis, since the activity of HOX proteins is highly cell and context dependent...
March 13, 2018: Stem Cell Reports
Safiyyah Ziyad, Jesse D Riordan, Ann M Cavanaugh, Trent Su, Gloria E Hernandez, Georg Hilfenhaus, Marco Morselli, Kristine Huynh, Kevin Wang, Jau-Nian Chen, Adam J Dupuy, M Luisa Iruela-Arispe
Given its role as the source of definitive hematopoietic cells, we sought to determine whether mutations initiated in the hemogenic endothelium would yield hematopoietic abnormalities or malignancies. Here, we find that endothelium-specific transposon mutagenesis in mice promotes hematopoietic pathologies that are both myeloid and lymphoid in nature. Frequently mutated genes included previously recognized cancer drivers and additional candidates, such as Pi4ka, a lipid kinase whose mutation was found to promote myeloid and erythroid dysfunction...
January 30, 2018: Cell Reports
Amanda D Yzaguirre, Elizabeth D Howell, Yan Li, Zijing Liu, Nancy A Speck
Hematopoietic cells differentiate during embryogenesis from a population of endothelial cells called hemogenic endothelium (HE) in a process called the endothelial-to-hematopoietic transition (EHT). The transcription factor Runx1 is required for EHT, but for how long and which endothelial cells are competent to respond to Runx1 are not known. Here, we show that the ability of Runx1 to induce EHT in non-hemogenic endothelial cells depends on the anatomical location of the cell and the developmental age of the conceptus...
January 29, 2018: Development
Claudia Gerri, Michele Marass, Andrea Rossi, Didier Y R Stainier
During development, hematopoietic stem cells (HSCs) derive from specialized endothelial cells (ECs) called hemogenic endothelium (HE) via a process called endothelial-to-hematopoietic transition (EHT). Hypoxia-inducible factor-1α (HIF-1α) has been reported to positively modulate EHT in vivo, but current data indicate the existence of other regulators of this process. Here we show that in zebrafish, Hif-2α also positively modulates HSC formation. Specifically, HSC marker gene expression is strongly decreased in hif -1aa;hif-1ab ( hif-1α ) and in hif-2aa;hif-2ab ( hif-2α ) zebrafish mutants and morphants...
March 1, 2018: Blood
Mathew G Angelos, Juan E Abrahante, Robert H Blum, Dan S Kaufman
Endothelial-to-hematopoietic transition (EHT) is an important stage in definitive hematopoietic development. However, the genetic mechanisms underlying human EHT remain poorly characterized. We performed single cell RNA-seq using 55 hemogenic endothelial cells (HECs: CD31+ CD144+ CD41- CD43- CD45- CD73- RUNX1c+ ), 47 vascular endothelial cells without hematopoietic potential (non-HE: CD31+ CD144+ CD41- CD43- CD45- CD73- RUNX1c- ), and 35 hematopoietic progenitor cells (HPCs: CD34+ CD43+ RUNX1c+ ) derived from human embryonic stem cells (hESCs)...
February 2018: Stem Cells
Valentina Sanghez, Anna Luzzi, Don Clarke, Dustin Kee, Steven Beuder, Danielle Rux, Mitsujiro Osawa, Joaquín Madrenas, Tsui-Fen Chou, Michael Kyba, Michelina Iacovino
Hemogenic endothelium (HE) undergoes endothelial-to-hematopoietic transition (EHT) to generate blood, a process that requires progressive down-regulation of endothelial genes and induction of hematopoietic ones. Previously, we have shown that the transcription factor HoxA3 prevents blood formation by inhibiting Runx1 expression, maintaining endothelial gene expression and thus blocking EHT. In the present study, we show that HoxA3 also prevents blood formation by inhibiting Notch pathway. HoxA3 induced upregulation of Jag1 ligand in endothelial cells, which led to cis-inhibition of the Notch pathway, rendering the HE nonresponsive to Notch signals...
2017: PloS One
Oscar Navarro-Montero, Veronica Ayllon, Mar Lamolda, Lourdes López-Onieva, Rosa Montes, Clara Bueno, Elizabeth Ng, Xiomara Guerrero-Carreno, Tamara Romero, Damià Romero-Moya, Ed Stanley, Andrew Elefanty, Verónica Ramos-Mejia, Pablo Menendez, Pedro J Real
Runt-related transcription factor 1 (Runx1) is a master hematopoietic transcription factor essential for hematopoietic stem cell (HSC) emergence. Runx1-deficient mice die during early embryogenesis due to the inability to establish definitive hematopoiesis. Here, we have used human pluripotent stem cells (hPSCs) as model to study the role of RUNX1 in human embryonic hematopoiesis. Although the three RUNX1 isoforms a, b, and c were induced in CD45+ hematopoietic cells, RUNX1c was the only isoform induced in hematoendothelial progenitors (HEPs)/hemogenic endothelium...
November 2017: Stem Cells
Joan P Zape, Carlos O Lizama, Kelly M Cautivo, Ann C Zovein
The emergence of haematopoietic stem and progenitor cells (HSPCs) from hemogenic endothelium results in the formation of sizeable HSPC clusters attached to the vascular wall. We evaluate the cell cycle and proliferation of HSPCs involved in cluster formation, as well as the molecular signatures from their initial appearance to the point when cluster cells are capable of adult engraftment (definitive HSCs). We uncover a non-clonal origin of HSPC clusters with differing cell cycle, migration, and cell signaling attributes...
October 2, 2017: Cell Cycle
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