Bi-Sen Ding

Bi-Sen Ding

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79
Publications
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5,549
Citations
Citations since 2017
21 Research Items
3663 Citations
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20172018201920202021202220230200400600
20172018201920202021202220230200400600
20172018201920202021202220230200400600

Publications

Publications (79)
Article
Despite the robust healing capacity of the liver, regenerative failure underlies numerous hepatic diseases, including the JAG1 haploinsufficient disorder, Alagille syndrome (ALGS). Cholestasis due to intrahepatic duct (IHD) paucity resolves in certain ALGS cases but fails in most with no clear mechanisms or therapeutic interventions. We find that m...
Article
The vasculature occupies a large area of the body, and none of the physiological activities can be carried out without blood vessels. Blood vessels are not just passive conduits and barriers for delivering blood and nutrients. Meanwhile, endothelial cells covering the vascular lumen establish vascular niches by deploying some growth factors, known...
Article
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Liver fibrosis is one main histological characteristic of nonalcoholic steatohepatitis (NASH), a disease paralleling a worldwide surge in metabolic syndromes with no approved therapies. The role of the gut microbiota in NASH pathogenesis has not been thoroughly illustrated, especially how the gut microbiota derives metabolites to influence the dist...
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Histone variants and the associated post-translational modifications that govern the stemness of haematopoietic stem cells (HSCs) and differentiation thereof into progenitors (HSPCs) have not been well defined. H3.3 is a replication-independent H3 histone variant in mammalian systems that is enriched at both H3K4me3- and H3K27me3-marked bivalent ge...
Article
Chronic hepatic diseases such as nonalcoholic steatohepatitis (NASH) suppress liver regeneration and lead to fibrosis and cirrhosis. Decoding the cellular and molecular network underlying this fibrotic maladaptation might aid in combatting NASH, a growing health challenge with no approved therapies. Here, we used multiomics analysis of human cirrho...
Article
Background & aims: Fibrosis in the liver is the main histological determinant of non-alcoholic steatohepatitis (NASH), a disease that parallels the worldwide surge in metabolic syndromes. Currently, there is no effective treatment for liver fibrosis. While Hippo/YAP (Yes-associated protein) signaling is essential for liver regeneration, its aberra...
Article
Chronic obstructive pulmonary disease (COPD) is marked by airway inflammation and airspace enlargement (emphysema) leading to airflow obstruction and eventual respiratory failure. Microvasculature dysfunction is associated with COPD/emphysema. However, it is not known if abnormal endothelium drives COPD/emphysema pathology and/or if correcting endo...
Article
Kidney fibrosis is accompanied by vascular dysfunction. Discovering new ways to ameliorate dysfunctional angiogenesis may bypass kidney fibrosis. YAP (Yes-associated protein) plays a multifaceted role during angiogenesis. Here, we found that selectively targeting YAP signaling in the endothelium ameliorates unilateral ureteral obstruction (UUO)-ind...
Article
Regenerative capacity is frequently impaired in aged organs. Stress to aged organs often causes scar formation (fibrosis) at the expense of regeneration. It remains to be defined how hematopoietic and vascular cells contribute to aging-induced regeneration to fibrotic transition. Here, we find that aging aberrantly reprograms the crosstalk between...
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Chromosome copy-number variations are a hallmark of cancer. Among them, the prevalent chromosome 17p deletions are associated with poor prognosis and can promote tumorigenesis more than TP53 loss. Here, we use multiple functional genetic strategies and identify a new 17p tumor suppressor gene (TSG), plant homeodomain finger protein 23 (PHF23). Its...
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ADAMTSs (A disintegrin and metalloproteinase with thrombospondin motifs) are secreted metalloproteinases that play a major role in the assembly and degradation of the extracellular matrix (ECM). In this study, we show that ADAMTS18, produced by the epithelial cells of distal airways and mesenchymal cells in lung apex at early embryonic stages, serv...
Article
Here, we show that the liver-derived apolipoprotein M (ApoM) protects the lung and kidney from pro-fibrotic insults and that this circulating factor is attenuated in aged mice. Aged mouse hepatocytes exhibit transcriptional suppression of ApoM. This leads to reduced sphingosine-1-phosphate (S1P) signaling via the S1P receptor 1 (S1PR1) in the vascu...
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Maintenance of adult tissues depends on stem cell self-renewal in local niches. Spermatogonial stem cells (SSC) are germline adult stem cells necessary for spermatogenesis and fertility. We show that testicular endothelial cells (TECs) are part of the SSC niche producing glial cell line-derived neurotrophic factor (GDNF) and other factors to suppor...
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Angiocrine factors, such as Notch ligands, supplied by the specialized endothelial cells (ECs) within the bone marrow and splenic vascular niche play an essential role in modulating the physiology of adult hematopoietic stem and progenitor cells (HSPCs). However, the relative contribution of various Notch ligands, specifically jagged-2, to the home...
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Background New data suggests that endothelial cells (ECs) elaborate essential “angiocrine factors”. The aim of this study is to investigate the role of activated ovarian endothelial cells in early in-vitro follicular development. Methods Mouse ovarian ECs were isolated using magnetic cell sorting or by FACS and cultured in serum free media. After...
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The regenerative capacity of lung and liver is sometimes impaired by chronic or overwhelming injury. Orthotopic transplantation of parenchymal stem cells to damaged organs might reinstate their self-repair ability. However, parenchymal cell engraftment is frequently hampered by the microenvironment in diseased recipient organs. We show that targeti...
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In mammals, the livers regenerate after chemical injury or resection of hepatic lobe by hepatectomy. How liver regeneration is initiated after mass loss remains to be defined. Here we report that following liver injury, activated platelets deploy SDF-1 and VEGF-A to stimulate CXCR7+ liver sinusoidal endothelial cell (LSEC) and VEGFR1+ myeloid cell,...
Article
Tumor-associated endothelial cells (TECs) regulate tumor cell aggressiveness. However, the core mechanism by which TECs confer stem cell-like activity to indolent tumors is unknown. Here, we used in vivo murine and human tumor models to identify the tumor-suppressive checkpoint role of TEC-expressed insulin growth factor (IGF) binding protein-7 (IG...
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Regeneration of hepatic sinusoidal vasculature is essential for non-fibrotic liver regrowth and restoration of its metabolic capacity. However, little is known about how this specialized vascular niche is regenerated. Here we show that activation of endothelial sphingosine-1-phosphate receptor-1 (S1P1) by its natural ligand bound to HDL (HDL-S1P) i...
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The transmembrane metalloprotease ADAM10 sheds a range of cell surface proteins, including ligands and receptors of the Notch, Eph, and erbB families, thereby activating signaling pathways critical for tumor initiation and maintenance. ADAM10 is thus a promising therapeutic target. Although widely expressed, its activity is normally tightly regulat...
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Current therapeutic approaches for treatment of exposure to radiation involve the use of antioxidants, chelating agents, recombinant growth factors and transplantation of stem cells (e.g., hematopoietic stem cell transplantation). However, exposure to high-dose radiation is associated with severe damage to the vasculature of vital organs, often lea...
Article
Endothelial cells that line capillaries are not just passive conduits for delivering blood. Tissue-specific endothelium establishes specialized vascular niches that deploy sets of growth factors, known as angiocrine factors. These cues participate actively in the induction, specification, patterning and guidance of organ regeneration, as well as in...
Article
Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury...
Article
Human airway basal cells (BC) are the stem/progenitor population of the airway epithelium, and play a central role in anchoring the epithelium to the basement membrane. The anatomic position of BC allows for potential paracrine signaling between BC and the underlying non-epithelial stromal cells. In support of this, we previously demonstrated endot...
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Anchoring pharmacologic agents to the vascular lumen has the potential to modulate critical processes at the blood-tissue interface, avoiding many of the off-target effects of systemically circulating agents. We report a novel strategy for endothelial dual targeting of therapeutics, which both enhances drug delivery and enables targeted agents to p...
Article
The lung alveoli regenerate after surgical removal of the left lobe by pneumonectomy (PNX). How this alveolar regrowth/regeneration is initiated remains unknown. We found that platelets trigger lung regeneration by supplying stromal-cell-derived factor-1 (SDF-1, also known as CXCL12). After PNX, activated platelets stimulate SDF-1 receptors CXCR4 a...
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Although endothelial cells have been shown to affect mouse pancreatic development, their precise function in human development remains unclear. Using a coculture system containing human embryonic stem cell (hESC)-derived progenitors and endothelial cells, we found that endothelial cells play a stage-dependent role in pancreatic development, in whic...
Article
Tumor endothelial cells (ECs) promote cancer progression in ways beyond their role as conduits supporting metabolism. However, it is unknown how vascular niche-derived paracrine factors, defined as angiocrine factors, provoke tumor aggressiveness. Here, we show that FGF4 produced by B cell lymphoma cells (LCs) through activating FGFR1 upregulates t...
Article
The ability to generate and maintain stable in vitro cultures of mouse endothelial cells (EC) has great potential for genetic dissection of the numerous pathologies involving vascular dysfunction as well as therapeutic applications. However, previous efforts at achieving sustained cultures of primary stable murine vascular cells have fallen short,...
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As the multipotent progenitor population of the airway epithelium, human airway basal cells (BC) replenish the specialized differentiated cell populations of the mucociliated airway epithelium during physiological turnover and repair. Cultured primary BC divide a limited number of times before entering a state of replicative senescence, preventing...
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Chemical or traumatic damage to the liver is frequently associated with aberrant healing (fibrosis) that overrides liver regeneration. The mechanism by which hepatic niche cells differentially modulate regeneration and fibrosis during liver repair remains to be defined. Hepatic vascular niche predominantly represented by liver sinusoidal endothelia...
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The use of targeted therapeutics to replenish pathologically deficient proteins on the luminal endothelial membrane has the potential to revolutionize emergency and cardiovascular medicine. Untargeted recombinant proteins, like activated protein C (APC) and thrombomodulin (TM), have demonstrated beneficial effects in acute vascular disorders, but h...
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Thrombomodulin (TM) is a glycoprotein normally present in the membrane of endothelial cells that binds thrombin and changes its substrate specificity to produce activated protein C (APC) that has anti-thrombotic and anti-inflammatory features. To compensate for loss of endogenous TM in pathology, we have fused recombinant TM with scFv fragment of a...
Article
Microvascular endothelial cells (ECs) within different tissues are endowed with distinct but as yet unrecognized structural, phenotypic, and functional attributes. We devised EC purification, cultivation, profiling, and transplantation models that establish tissue-specific molecular libraries of ECs devoid of lymphatic ECs or parenchymal cells. The...
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In glioblastoma high expression of the CD133 gene, also called Prominin1, is associated with poor prognosis. The PDGF-driven proneural group represents a subset of glioblastoma in which CD133 is not overexpressed. Interestingly, this particular subset shows a relatively good prognosis. As with many other tumors, gliobastoma is believed to arise and...
Data
(A) Relative quantification of gene expression levels determined by qPCR of Prom1+ and Prom1− cells at day 0 and after 6 days in culture under stem cell conditions. In each graph the level of expression of Prom1− cells is set to 100% and is not shown. The relative amount of expression in Prom1+ versus is Prom1− is shown in percentage. Confocal imag...
Data
Characteristics of tumor derived from Prom1+ cells and Prom1− cells. (A) H&E section of tumor derived from Prom1+ neurospheres revealed pseudopalisading necrosis (pp) and microvascular proliferation “glomeruloid tuft” (gt). H&E section of tumors derived from Prom1− neurospheres included (B) pseudopalisading necrosis and (C) microvascular hyperplasi...
Data
List of primers used for qPCR. (DOCX)
Data
qPCR validation of selected genes from Prom1+ endothelial cells. (TIFF)
Data
X-gal staining detects Prom1+ cells from the ependyma to the olfactory bulb of the brain of an eight-week old Prom1lacZ/+ mouse model. (a and c, left panel) Low-power and respective magnified images (b and d, right panel) of anteroposterior coronal sections showing the distribution of ß-galactosidase activity in the olfactory bulb (a and b), and co...
Data
Prom1+ cells are detected in the forebrain of Prom1lacZ/+ adult mice. Z-stack confocal images revealed coimmunostaining for ß-galactosidase (green) and calretinin (red) neurons in the olfactory bulb (A), doublecortin neuroblasts (red) in the SVZ and in RMS (B), GFAP (red) large astrocytic cells in the SVZ area (C), CD24 (red) ependymal cells (D) an...
Chapter
Endothelial cells not only form the vascular networks that deliver nutrients and oxygen throughout the body, they also establish instructive niches that stimulate organ regeneration through elaboration of paracrine trophogens. Priming of the vascular niche promotes repair and regeneration of damaged tissues by establishing an inductive vascular net...
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Full-text available
Unlabelled: Several studies have demonstrated that hematopoietic cells originate from endotheliumin early development; however, the phenotypic progression of progenitor cells during human embryonic hemogenesis is not well described. Here, we define the developmental hierarchy among intermediate populations of hematopoietic progenitor cells (HPCs)...
Article
ETS transcription factors ETV2, FLI1, and ERG1 specify pluripotent stem cells into induced vascular endothelial cells (iVECs). However, iVECs are unstable and drift toward nonvascular cells. We show that human midgestation c-Kit(-) lineage-committed amniotic cells (ACs) can be reprogrammed into vascular endothelial cells (rAC-VECs) without transiti...
Article
During angiogenesis, nascent vascular sprouts fuse to form vascular networks, enabling efficient circulation. Mechanisms that stabilize the vascular plexus are not well understood. Sphingosine 1-phosphate (S1P) is a blood-borne lipid mediator implicated in the regulation of vascular and immune systems. Here we describe a mechanism by which the G pr...
Article
Thrombin generates fibrin and activates platelets and endothelium, causing thrombosis and inflammation. Endothelial thrombomodulin (TM) changes thrombin's substrate specificity toward cleavage of plasma protein C into activated protein C (APC), which opposes its thrombotic and inflammatory activities. Endogenous TM activity is suppressed in patholo...
Article
The New York Stem Cell Foundation's "Sixth Annual Translational Stem Cell Research Conference" convened on October 11-12, 2011 at the Rockefeller University in New York City. Over 450 scientists, patient advocates, and stem cell research supporters from 14 countries registered for the conference. In addition to poster and platform presentations, th...
Article
The human airway epithelium is a pseudostratified heterogenous layer comprised of ciliated, secretory, intermediate, and basal cells. As the stem/progenitor population of the airway epithelium, airway basal cells differentiate into ciliated and secretory cells to replenish the airway epithelium during physiological turnover and repair. Transcriptom...
Article
Full-text available
Advances in the treatment of acute leukemia have resulted in significantly improved remission rates, although disease relapse poses a significant risk. By utilizing sensitive, non-invasive imaging guidance, detection of early leukemic infiltration and the extent of residual tumor burden after targeted therapy can be expedited, leading to more effic...
Article
Patients with HIV-1 immune-related thrombocytopenia (HIV-1-ITP) have a unique antibody (Ab) against platelet GPIIIa49-66, which is capable of inducing oxidative platelet fragmentation in the absence of complement activation. By screening a human phage antibody library with the GPIIIa49-66 peptide as bait, we have developed several humanized phage A...
Article
To identify pathways involved in adult lung regeneration, we employ a unilateral pneumonectomy (PNX) model that promotes regenerative alveolarization in the remaining intact lung. We show that PNX stimulates pulmonary capillary endothelial cells (PCECs) to produce angiocrine growth factors that induce proliferation of epithelial progenitor cells su...
Article
Full-text available
During embryogenesis, endothelial cells induce organogenesis before the development of circulation. These findings suggest that endothelial cells not only form passive conduits to deliver nutrients and oxygen, but also establish an instructive vascular niche, which through elaboration of paracrine trophogens stimulates organ regeneration, in a mann...
Article
Full-text available
Endothelial cells establish an instructive vascular niche that reconstitutes haematopoietic stem and progenitor cells (HSPCs) through release of specific paracrine growth factors, known as angiocrine factors. However, the mechanism by which endothelial cells balance the rate of proliferation and lineage-specific differentiation of HSPCs is unknown....
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The Silences of the Archives, the Reknown of the Story. The Martin Guerre affair has been told many times since Jean de Coras and Guillaume Lesueur published their stories in 1561. It is in many ways a perfect intrigue with uncanny resemblance, persuasive deception and a surprizing end when the two Martin stood face to face, memory to memory, befor...
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Chemical coupling to carrier red blood cells (RBCs) converts tissue type plasminogen activator (tPA) from a problematic therapeutic into a safe agent for thromboprophylaxis. The goal of this study was to develop a more clinically relevant recombinant biotherapeutic by fusing a mutant tPA with a single-chain antibody fragment (scFv) with specificity...
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Endothelial thrombomodulin (TM) regulates thrombosis and inflammation. Diverse forms of pulmonary and vascular injury are accompanied by down-regulation of TM, which aggravates tissue injury. We postulated that anchoring TM to the endothelial surface would restore its protective functions. To design an effective and safe strategy to treat pulmonary...
Article
Cerebrovascular thrombosis is a major source of morbidity and mortality after surgery, but thromboprophylaxis in this setting is limited because of the formidable risk of perioperative bleeding. Thrombolytics (eg, tissue-type plasminogen activator [tPA]) cannot be used prophylactically in this high-risk setting because of their short duration of ac...
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The endothelium is a target for therapeutic and diagnostic interventions in a plethora of human disease conditions including ischemia, inflammation, edema, oxidative stress, thrombosis and hemorrhage, and metabolic and oncological diseases. Unfortunately, drugs have no affinity to the endothelium, thereby limiting the localization, timing, specific...
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A recombinant prodrug, single-chain urokinase-type plasminogen activator (scuPA) fused to an anti-PECAM-1 antibody single-chain variable fragment (anti-PECAM scFv/scuPA) targets endothelium and augments thrombolysis in the pulmonary vasculature.(1) To avoid premature activation and inactivation and to limit systemic toxicity, we replaced the native...
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Efficacy and safety of current means to prevent cerebrovascular thrombosis in patients at high risk of stroke are suboptimal. In theory, anchoring fibrinolytic plasminogen activators to the luminal surface of the cerebral endothelium might arrest formation of occlusive clots in this setting. We tested this approach using the recombinant construct a...