Contribution of the vascular niche to the hematopoietic reconstitution.

血管生态位对造血重建的贡献。

• 批准号: 8308408
• 负责人: Shahin Rafii
• 金额: $ 41.52万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-05 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308408
• 关键词: Ablation; Adenovirus Vector; Adult; Angiogenic Factor; Aplastic Anemia; Area; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; CXCL12 gene; CXCR4 gene; Calcified; Cells; Commit; Data; Dysmyelopoietic Syndromes; Endothelial Cells; Engraftment; Failure; Fibroblast Growth Factor 2; Flow Cytometry; Fluorouracil; Generations; Genes; Genetic; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Homeostasis; Human; In Vitro; Injection of therapeutic agent; Knockout Mice; Limb structure; Location; Maintenance; Manuscripts; Mediating; Modeling; Molecular; Molecular Profiling; Monoclonal Antibodies; Mus; Myelogenous; Myelosuppression; Natural regeneration; PGF gene; Pancytopenia; Pathway interactions; Physiological; Platelet Count measurement; Play; Preparation; Protein Isoforms; Receptor Protein-Tyrosine Kinases; Recovery; Relative (related person); Reporter; Role; Serum; Signal Transduction; Smooth Muscle; Spleen; Stem Cell Factor; Stem cells; Stromal Cell-Derived Factor 1; Supporting Cell; Surface; Testing; Thrombopoietin; Thrombospondin 1; Tissues; Transplantation; Uncertainty; VEGF165; VEGF189; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-3; Vascular Endothelial Growth Factors; Vascularization; Work; angiogenesis; arteriole; base; cadherin 5; cell type; chemotherapy; cytokine; irradiation; knock-down; neutralizing monoclonal antibodies; novel; progenitor; promoter; proto-oncogene protein kfgf; public health relevance; receptor; reconstitution; reconstruction; restoration; self-renewal

DESCRIPTION (provided by applicant): Accumulating evidence from our group and others suggest that bone marrow (BM) sinusoidal endothelial cells (SECs) represent a dynamic "vascular niche", which may provide the cellular platform for the reconstitution of hematopoiesis after myelosuppression. Using technical advances in bone marrow (BM) preparation, we have recently established a comprehensive phenotypic and functional signature of BM SECs at steady state and during hemangiogenic regeneration. We have recently shown that, after moderate to severe myelosuppression rapid regeneration of the regressed SECs is essential for engraftment and replenishment of the transplanted long-term hematopoietic stem cells (LT-HSCs) and reconstitution of hematopoiesis. Most likely, transplanted HSC and their lineage committed hematopoietic progenitor cells (HPCs) by releasing of neo- angiogenic factors contribute to the regeneration of SEC. However, the precise mechanism by which angiogenic factors released by the pro-angiogenic hematopoietic cells, such as CXCR4+VEGFR1+ myeloid and megakaryocytic progenitors cells support reconstruction of the SECs is not known. The broad long-term objective of this proposal is to identify the molecular pathways and to define the mechanism whereby angiogenic factors, specifically the VEGF-A isoforms, PlGF and SDF1 elaborated by specific subsets of the hematopoietic cells support assembly and remodeling of BM's "Vascular Niche", thereby supporting reconstitution of HSCs and hematopoiesis after myelosuppression. Therefore, we hypothesize that within BM, the VE- cadherin+VEGFR2+VEGFR3+Sca1- SECs establish a vascular niche, which is a dynamic cellular microenvironment essential for the reconstitution of HSC, and hematopoiesis after myelosuppression. Regenerating pro-angiogenic CXCR4+VEGFR1+ hematopoietic cells through release of VEGF-A SDF-1, and as yet unrecognized angiogenic factors accelerate regeneration of the SECs thereby accelerating the reconstitution of the LT- HSCs and hematopoiesis. This hypothesis will be tested through: 1) determining the mechanism by which pro-angiogenic hematopoietic cells by elaborating VEGF-A and SDF-1 support the regeneration of regressed SECs thereby reconstituting LT-HSCs and hematopoiesis: 2) assessing the relative contribution of preexisting CXCR4+ endothelial cells versus transplanted CXCR4+VEGFR1+ hematopoietic cells to the revascularization of the ischemic limbs and 3) evaluating the physiological significance of enforced expression of angiogenic factors in accelerating the regeneration of BM SECs and reconstitution of hematopoiesis. We anticipate that understanding the mechanism by which angiogenic factors regulate hematopoiesis and HSC self-renewal will offer new strategies to treat BM failure states, including aplastic anemia, myelodysplastic syndromes and accelerate BM reconstitution after chemotherapy, irradiation and transplantation. PUBLIC HEALTH RELEVANCE: We hypothesize that bone marrow's vascular niche is a dynamic cellular microenvironment that is essential for the maintenance and reconstitution of hematopoiesis after myelosuppression. Regenerating CXCR4+VEGFR1+ hematopoietic cells through release of angiogenic factors, including VEGF-A, PlGF, SDF-1 and FGF-2 support regeneration of the sinusoidal endothelial cells into functional vascular niche thereby accelerating the restoration of hematopoietic stem cells and reconstitution of hematopoiesis. We anticipate that understanding the mechanism by which angiogenic factors regulate the reconstruction of the vascular niche in the bone marrow will offer new strategies to treat hematopoietic failure states, including aplastic anemia, myelodysplastic syndromes and accelerate BM reconstitution after chemotherapy, irradiation and bone marrow transplantation.

描述（由申请人提供）：我们小组和其他人的积累证据表明，骨髓（BM）正弦内皮细胞（SECS）代表动态的“血管生态位”，这可能为髓鞘抑制后的造血基础提供一个细胞平台。使用骨髓（BM）制剂中的技术进步，我们最近在稳态和造血再生过程中建立了BM SEC的全面表型和功能特征。我们最近表明，在中度至重度骨髓抑制后，回归的SECS快速再生对于移植和补充移植的长期造血干细胞（LT-HSC）和造血基础的重新建立至关重要。通过释放新的血管生成因子有助于SEC的再生，最有可能的是移植的HSC及其谱系所承诺的造血祖细胞（HPC）。然而，尚不清楚SEC的重建，由促血管生成造血细胞释放的血管生成因子（例如CXCR4+ VEGFR1+髓样祖细胞）的精确机制。 The broad long-term objective of this proposal is to identify the molecular pathways and to define the mechanism whereby angiogenic factors, specifically the VEGF-A isoforms, PlGF and SDF1 elaborated by specific subsets of the hematopoietic cells support assembly and remodeling of BM's "Vascular Niche", thereby supporting reconstitution of HSCs and hematopoiesis after myelosuppression.因此，我们假设在BM中，Ve-Cadherin+VEGFR2+VEGFR3+SCA1- SECS建立了一个血管生态裂，这是一种动态的细胞微环境，对于HSC的重新基础和骨髓抑制后的血肿。通过释放VEGF-A SDF-1的释放，再生促血管生成的CXCR4+ VEGFR1+造血细胞，并且尚未识别的SECS的血管生成因子加速了SEC的再生，从而加速了LT-HSCS和hscopoiesis的重新确定。该假设将通过：1）确定通过详细说明VEGF-A和SDF-1支持促血管生成造血细胞的机制，以支持回归的SEC的再生，从而重新建立了LT-HSCS和造血性，从而重新构成secs：2）评估PREESED+ cxcr4+ cccr4+ ver 4+ ver 4+ sellants+ ver insprus vers vers+ ver 4造血细胞是缺血性肢体血运重建的，3）评估血管生成因子在加速BM SEC的再生和重新结构造血的生理意义上的生理意义。我们预计，了解血管生成因子调节造血和HSC自我更新的机制将为治疗BM衰竭状态提供新的策略，包括性障碍性贫血，骨髓增生综合症，并在化学疗法，辐射和辐射后加速BM重组。 公共卫生相关性：我们假设骨髓的血管生态位是一种动态的细胞微环境，对于骨髓抑制后的维持和重建是至关重要的。通过释放包括VEGF-A，PLGF，SDF-1和FGF-2在内的血管生成因子的再生CXCR4+ VEGFR1+造血细胞的再生，这支持正弦内皮内皮细胞的再生，从而加速了血管造血细胞的功能性血管niche，从而加速了血肿细胞和重新养生型乳糖菌的恢复。我们预计，了解血管生成因子调节骨髓中血管生态位的重建的机制将提供新的策略，以治疗血管衰竭状态，包括性障碍性贫血，骨髓异常综合症，骨髓异常综合征和加速后BM重新分配后，在化学疗法，放射，放射和骨骼摩根后进行了重新分配。

项目成果

Efficient direct reprogramming of mature amniotic cells into endothelial cells by ETS factors and TGFβ suppression.

• DOI: 10.1016/j.cell.2012.09.032
• 发表时间: 2012-10-26
• 期刊: Cell
• 影响因子: 64.5
• 作者: Ginsberg M;James D;Ding BS;Nolan D;Geng F;Butler JM;Schachterle W;Pulijaal VR;Mathew S;Chasen ST;Xiang J;Rosenwaks Z;Shido K;Elemento O;Rabbany SY;Rafii S
• 通讯作者: Rafii S

Direct conversion of human amniotic cells into endothelial cells without transitioning through a pluripotent state.

• DOI: 10.1038/nprot.2015.126
• 发表时间: 2015-12
• 期刊: Nature protocols
• 影响因子: 14.8
• 作者: Ginsberg M;Schachterle W;Shido K;Rafii S
• 通讯作者: Rafii S

Molecular Checkpoint Decisions Made by Subverted Vascular Niche Transform Indolent Tumor Cells into Chemoresistant Cancer Stem Cells.

• DOI: 10.1016/j.ccell.2016.11.010
• 发表时间: 2017-01-09
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Cao Z;Scandura JM;Inghirami GG;Shido K;Ding BS;Rafii S
• 通讯作者: Rafii S

Activation of the vascular niche supports leukemic progression and resistance to chemotherapy.

• DOI: 10.1016/j.exphem.2014.08.003
• 发表时间: 2014-11
• 期刊: EXPERIMENTAL HEMATOLOGY
• 影响因子: 2.6
• 作者: Poulos, Michael G.;Gars, Eric J.;Gutkin, Michael C.;Kloss, Christopher C.;Ginsberg, Michael;Scandura, Joseph M.;Rafii, Shahin;Butler, Jason M.
• 通讯作者: Butler, Jason M.

Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis.

针对血管和血管周围生态位作为肺和肝纤维化的再生疗法

• DOI: 10.1126/scitranslmed.aai8710
• 发表时间: 2017-08-30
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Cao Z;Ye T;Sun Y;Ji G;Shido K;Chen Y;Luo L;Na F;Li X;Huang Z;Ko JL;Mittal V;Qiao L;Chen C;Martinez FJ;Rafii S;Ding BS
• 通讯作者: Ding BS