scholarly journals A Murine Model With JAK2V617F Expression in Both Hematopoietic Cells and Vascular Endothelial Cells Recapitulates the Key Features of Human Myeloproliferative Neoplasm

2021 ◽  
Vol 11 ◽  
Author(s):  
Haotian Zhang ◽  
Amar Yeware ◽  
Sandy Lee ◽  
Huichun Zhan
Keyword(s):  
Endothelial Cells ◽  
Disease Progression ◽  
Murine Model ◽  
Vascular Endothelial Cells ◽  
Hematopoietic Cells ◽  
Cardiovascular Complications ◽  
Vascular Endothelial ◽  
Hematopoietic Stem ◽  
Cell Functions ◽  
Key Features

The myeloproliferative neoplasms (MPNs) are characterized by an expansion of the neoplastic hematopoietic stem/progenitor cells (HSPC) and an increased risk of cardiovascular complications. The acquired kinase mutation JAK2V617F is present in hematopoietic cells in a majority of patients with MPNs. Vascular endothelial cells (ECs) carrying the JAK2V617F mutation can also be detected in patients with MPNs. In this study, we show that a murine model with both JAK2V617F-bearing hematopoietic cells and JAK2V617F-bearing vascular ECs recapitulated all the key features of the human MPN disease, which include disease transformation from essential thrombocythemia to myelofibrosis, extramedullary splenic hematopoiesis, and spontaneous cardiovascular complications. We also found that, during aging and MPN disease progression, there was a loss of both HSPC number and HSPC function in the marrow while the neoplastic hematopoiesis was relatively maintained in the spleen, mimicking the advanced phases of human MPN disease. Different vascular niche of the marrow and spleen could contribute to the different JAK2V617F mutant stem cell functions we have observed in this JAK2V617F-positive murine model. These results indicate that the spleen is functionally important for the JAK2V617F mutant neoplastic hematopoiesis during aging and MPN disease progression. Compared to other MPN murine models reported so far, our studies demonstrate that JAK2V617F-bearing vascular ECs play an important role in both the hematologic and cardiovascular abnormalities of MPN.

scholarly journals A murine model with JAK2V617F expression in both hematopoietic cells and vascular endothelial cells recapitulates the key features of human myeloproliferative neoplasm

2021 ◽  
Author(s):  
Haotian Zhang ◽  
Amar Yeware ◽  
Sandy Lee ◽  
Huichun Zhan
Keyword(s):  
Endothelial Cells ◽  
Murine Model ◽  
Vascular Endothelial Cells ◽  
Hematopoietic Cells ◽  
Cardiovascular Complications ◽  
Vascular Endothelial ◽  
Hematopoietic Stem ◽  
Cell Functions ◽  
Increased Risk ◽  
Key Features

The myeloproliferative neoplasms (MPNs) are characterized by an expansion of the neoplastic hematopoietic stem/progenitor cells (HSPC) and an increased risk of cardiovascular complications. The acquired kinase mutation JAK2V617F is present in hematopoietic cells in a majority of patients with MPNs. Vascular endothelial cells (ECs) carrying the JAK2V617F mutation can also be detected in patients with MPNs. In this study, we show that a murine model with both JAK2V617F-bearing hematopoietic cells and JAK2V617F bearing vascular ECs recapitulated all the key features of the human MPN disease, which include disease transformation from essential thrombocythemia to myelofibrosis, extramedullary splenic hematopoiesis, and spontaneous cardiovascular complications. During aging and MPN disease progression, there was a loss of both HSPC number and HSPC function in the marrow while the neoplastic hematopoiesis was relatively maintained in the spleen, mimicking the advanced phases of human MPN disease. Different vascular niche of the marrow and spleen could contribute to the different JAK2V617F mutant stem cell functions we have observed in this JAK2V617F-positive murine model. Compared to other MPN murine models reported so far, our studies demonstrate that endothelial dysfunction plays an important role in both the hematologic and cardiovascular abnormalities of MPN.

scholarly journals Effect of Hyperglycemia on Epcs Function and Regenerative Ability

2020 ◽  
Author(s):  
Hadeel Khalil Hendawi ◽  
Dina Nehad Awartani ◽  
Aya Ghoul ◽  
Isra Marei
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Barrier Function ◽  
Vascular Endothelial Cells ◽  
Vascular Dysfunction ◽  
Vascular Complications ◽  
Cardiovascular Complications ◽  
Diabetic Patients ◽  
Vascular Endothelial ◽  
Cell Functions

Diabetes induced hyperglycemia increases the risk of cardiovascular complications as it impacts vascular endothelial cells causing vascular dysfunction. Endothelial progenitor cells (EPCs) have been suggested to participate in the repair of vascular endothelial cells once they are impacted by hyperglycemia in diabetic patients. This research aims to test the EPC subtype blood outgrowth endothelial cells (BOECs) and their ability to survive and function under chronic hyperglycemic conditions. For that, we studied BOECs viability, response to shear stress, angiogenesis ability, and barrier function under normoglycemic (5.5mM) and hyperglycemic (25mM) conditions. The results have shown significant effects of chronic hyperglycemic conditions on cell proliferation (n=3, p<0.05), and migration (n=3, p<0.05) which were decreased when compared to control. Cells responses to shear stress were not affected under these conditions. There was a trend towards an increase in permeability as indicated by barrier function assays. The decrease in those endothelial cell functions might impact the repair mechanisms needed in diabetic patients to protect from vascular complications. Further investigations are required to establish therapeutic targets to improve EPCs repair function.

scholarly journals Generation of Vascular Endothelial Cells and Hematopoietic Cells by Blastocyst Complementation

2018 ◽  
Vol 11 (4) ◽  
pp. 988-997 ◽  
Author(s):  
Sanae Hamanaka ◽  
Ayumi Umino ◽  
Hideyuki Sato ◽  
Tomonari Hayama ◽  
Ayaka Yanagida ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Hematopoietic Cells ◽  
Vascular Endothelial ◽  
Blastocyst Complementation

scholarly journals Anticoagulant Therapy for Patients with Coronavirus Disease 2019: Urgent Need for Enhanced Awareness

2020 ◽  
Vol 15 ◽  
Author(s):  
Maki Komiyama ◽  
Koji Hasegawa
Keyword(s):  
Endothelial Cells ◽  
Anticoagulant Therapy ◽  
Retrospective Studies ◽  
Vascular Endothelial Cells ◽  
Therapeutic Option ◽  
Cardiovascular Complications ◽  
Vascular Endothelial ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Global Pandemic

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic. SARS-CoV-2 binds to the angiotensin-converting enzyme 2 receptor, which is abundantly expressed in vascular endothelial cells and damages these cells. Besides pneumonia-induced respiratory failure, thrombotic cardiovascular complications are increasingly emerging as a major COVID-19 symptom. Multiple retrospective studies have strongly suggested that anticoagulant therapy improves the prognosis of people with COVID-19. However, validation of the safety and effectiveness of anticoagulant therapy for COVID-19 and greater awareness of this clinical therapeutic option are urgently needed.

Hematopoietic Stem Cells Contribute to Lymphatic Endothelium.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1658-1658
Author(s):  
Shuguang Jiang ◽  
Alexis S. Bailey ◽  
John R. Swain ◽  
Erin M. Hewett ◽  
Melissa H. Wong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Hematopoietic Stem Cells ◽  
Progenitor Cells ◽  
Vascular Endothelial Cells ◽  
Lymphatic Vessels ◽  
Vascular Endothelial ◽  
Lymphatic Endothelium ◽  
Hematopoietic Stem ◽  
Impaired Wound Healing

Abstract The lymphatic system plays an important physiological role in vascular and immune homeostasis. Lymphatic vessel function is implicated in a number of pathological conditions including tumor metastasis and impaired wound healing. The identity and origin of lymphatic endothelial precursors is poorly understood. Previously we have shown that adult bone marrow-derived, hematopoietic stem cells (HSCs, c-kit+, Sca-1+, lineage−) can differentiate into functional blood vascular endothelial cells. Given the close relationship between the blood and lymphatic vascular systems, we have investigated whether HSCs also give rise to lymphatic endothelial cells (LEC). GFP+ HSCs were transplanted into lethally irradiated (1200 cGy) recipient mice. Donor-derived LEC expressing lymphatic endothelial markers including LYVE-1 and VEGFR3 were clearly distinguished from hematopoietic cells by the absence of CD45 and F4/80 expression. Deconvolution microscopy confirmed the co-localization of donor and LEC marker expression in individual cells. Transplanted HSCs gave rise to LEC in the liver, gut, gastric and kidney. Donor-derived LEC were detected in 2.4% of liver lymphatic vessels at 4 weeks and persisted for at least 12 months (mean of 3.4%). The self-renewal capacity of HSC-derived lymphatic progenitor cells was demonstrated by serial transplantation. The contribution of these progenitors to tumor lymphatics was evaluated. Transplantation of HSCs into young Min−/− mice resulted in the incorporation of donor-derived LEC into the lymphatics of intestinal adenomas that spontaneously develop in these mice. In addition, CD45+F4/80+ leukocytes were detected in the vessel lumens indicating that these are functional tumor lymphatic vessels. Finally, to determine if LEC progenitors contribute to lymphatic vessels in the absence of radiation injury or tumorigenesis, a parabiosis model was evaluated. Donor-derived LEC were detected in parabiotic mice at a frequency similar to that observed for donor-derived blood vascular endothelial cells. This finding suggests that circulating progenitor cells contribute to lymphangiogenesis during steady-state conditions. Our results indicate that hematopoietic stem cells have the potential to contribute to lymphatic endothelium and therefore HSC-derived progenitors may be potential therapeutic targets for hematopoietic and lymphatic disease.

scholarly journals Endothelial JAK2V617F mutation leads to thrombosis, vasculopathy, and cardiomyopathy in a murine model of myeloproliferative neoplasm

2019 ◽  
Author(s):  
Melissa Castiglione ◽  
Christopher Mazzeo ◽  
Ya-Ping Jiang ◽  
Juei-Suei Chen ◽  
Kenneth Kaushansky ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Murine Model ◽  
Blood Cells ◽  
Cardiovascular Complications ◽  
Jak2v617f Mutation ◽  
Vascular Endothelial ◽  
Hematopoietic Stem ◽  
Endothelial Cell Function ◽  
Left Ventricle Remodeling ◽  
Increased Risk

ABSTRACTRationalThe myeloproliferative neoplasms (MPNs) are clonal hematological malignancies characterized by hematopoietic stem cell expansion and overproduction of mature blood cells. Cardiovascular complications are the leading cause of morbidity and mortality in patients with MPNs. The acquired kinase mutation JAK2V617F plays a central role in these disorders. Mechanisms responsible for cardiovascular dysfunction in MPNs are not fully understood, limiting the effectiveness of current treatment.ObjectiveVascular endothelial cells (ECs) play critical roles in the regulation of hemostasis and thrombosis. ECs carrying the JAK2V617F mutation can be detected in patients with MPNs. The goal of this study was to test the hypothesis that the JAK2V617F mutation alters endothelial function to promote cardiovascular complications in patients with MPNs.Methods and ResultsWe employed murine models of MPN in which the JAK2V617F mutation is expressed in specific cell lineages. When JAK2V617F is expressed in both blood cells and vascular ECs, the mice developed MPN and spontaneous, age-related dilated cardiomyopathy with an increased risk of sudden death as well as a prothrombotic and vasculopathy phenotype on histology evaluation. We showed that JAK2V617F-mutant ECs are required for this cardiovascular disease phenotype and the mutation can alter endothelial cell function. Finally, in a more therapeutically oriented approach, we demonstrated that transplantation with wild-type donor marrow cells can improve cardiac function by reversing the left ventricle remodeling process in this JAK2V617F-positive MPN murine model.ConclusionsThese findings suggest that the JAK2V617F mutation alters vascular endothelial function to promote cardiovascular complications in MPNs. Therefore, targeting the MPN vasculature represents a promising new therapeutic strategy for patients with MPNs.

The Dynamic Response of Vascular Endothelial Cells to Fluid Shear Stress

1981 ◽  
Vol 103 (3) ◽  
pp. 177-185 ◽  
Author(s):  
C. F. Dewey ◽  
S. R. Bussolari ◽  
M. A. Gimbrone ◽  
P. F. Davies
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Endothelial Cell ◽  
Dynamic Response ◽  
Fluid Shear Stress ◽  
Vascular Endothelial Cells ◽  
Shear Stresses ◽  
Vascular Endothelial ◽  
Fluid Shear ◽  
Cell Functions

We have developed an in-vitro system for studying the dynamic response of vascular endothelial cells to controlled levels of fluid shear stress. Cultured monolayers of bovine aortic endothelial cells are placed in a cone-plate apparatus that produces a uniform fluid shear stress on replicate samples. Subconfluent endothelial cultures continuously exposed to 1–5 dynes/cm2 shear proliferate at a rate comparable to that of static cultures and reach the same saturation density (≃ 1.0–1.5 × 105 cells/cm2). When exposed to a laminar shear stress of 5–10 dynes/cm2, confluent monolayers undergo a time-dependent change in cell shape from polygonal to ellipsoidal and become uniformly oriented with flow. Regeneration of linear “wounds” in confluent monolayer appears to be influenced by the direction of the applied force. Preliminary studies indicate that certain endothelial cell functions, including fluid endocytosis, cytoskeletal assembly and nonthrombogenic surface properties, also are sensitive to shear stress. These observations suggest that fluid mechanical forces can directly influence endothelial cell structure and function. Modulation of endothelial behavior by fluid shear stresses may be relevant to normal vessel wall physiology, as well as the pathogenesis of vascular diseases, such as atherosclerosis.

scholarly journals Vascular Notch Signaling in Stress Hematopoiesis

2021 ◽  
Vol 8 ◽  
Author(s):  
Can Huang ◽  
Dawei Yang ◽  
George W. Ye ◽  
Charles A. Powell ◽  
Peipei Guo
Keyword(s):  
Endothelial Cells ◽  
Notch Signaling ◽  
Cell Fate ◽  
Stromal Cell ◽  
Vascular Endothelial Cells ◽  
Cell Lineage ◽  
Transgenic Animals ◽  
Cell Types ◽  
Vascular Endothelial ◽  
Hematopoietic Stem

Canonical Notch signaling is one of the most conserved signaling cascades. It regulates cell proliferation, cell differentiation, and cell fate maintenance in a variety of biological systems during development and cancer (Fortini, 2009; Kopan and Ilagan, 2009; Andersson et al., 2011; Ntziachristos et al., 2014). For the hematopoietic system, during embryonic development, Notch1 is essential for the emergence of hematopoietic stem cells (HSCs) at the aorta-gornado-mesonephro regions of the dorsal aorta. At adult stage, Notch receptors and Notch targets are expressed at different levels in diverse hematopoietic cell types and influence lineage choices. For example, Notch specifies T cell lineage over B cells. However, there has been a long-lasting debate on whether Notch signaling is required for the maintenance of adult HSCs, utilizing transgenic animals inactivating different components of the Notch signaling pathway in HSCs or niche cells. The aims of the current mini-review are to summarize the evidence that disapproves or supports such hypothesis and point at imperative questions waiting to be addressed; hence, some of the seemingly contradictory findings could be reconciled. We need to better delineate the Notch signaling events using biochemical assays to identify direct Notch targets within HSCs or niche cells in specific biological context. More importantly, we call for more elaborate studies that pertain to whether niche cell type (vascular endothelial cells or other stromal cell)-specific Notch ligands regulate the differentiation of T cells in solid tumors during the progression of T-lymphoblastic lymphoma (T-ALL) or chronic myelomonocytic leukemia (CMML). We believe that the investigation of vascular endothelial cells' or other stromal cell types' interaction with hematopoietic cells during homeostasis and stress can offer insights toward specific and effective Notch-related therapeutics.

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