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）：我们小组和其他人积累的证据表明，骨髓（BM）窦状内皮细胞（SEC）代表了一个动态的“血管生态位”，这可能为骨髓抑制后重建造血功能提供细胞平台。利用骨髓 (BM) 制备方面的技术进步，我们最近建立了稳定状态和血管生成再生过程中 BM SEC 的全面表型和功能特征。我们最近发现，中度至重度骨髓抑制后，退化的 SEC 的快速再生对于移植的长期造血干细胞 (LT-HSC) 的植入和补充以及造血功能的重建至关重要。最有可能的是，移植的 HSC 及其谱系定向造血祖细胞 (HPC) 通过释放新血管生成因子有助于 SEC 的再生。然而，促血管生成造血细胞（例如 CXCR4+VEGFR1+ 骨髓和巨核祖细胞）释放的血管生成因子支持 SEC 重建的确切机制尚不清楚。该提案的广泛长期目标是确定分子途径并定义血管生成因子（特别是由特定造血细胞亚群阐述的 VEGF-A 同工型、PlGF 和 SDF1）支持 BM“血管”组装和重塑的机制。 Niche”，从而支持骨髓抑制后 HSC 和造血的重建。因此，我们假设在BM内，VE-cadherin+VEGFR2+VEGFR3+Sca1-SEC建立了一个血管生态位，这是一个动态的细胞微环境，对于骨髓抑制后HSC的重建和造血至关重要。通过释放 VEGF-A SDF-1 和尚未识别的血管生成因子来再生促血管生成 CXCR4+VEGFR1+ 造血细胞，加速 SEC 的再生，从而加速 LT-HSC 和造血的重建。该假设将通过以下方式进行检验：1) 通过精心设计 VEGF-A 和 SDF-1 来确定促血管生成造血细胞支持退化 SEC 的再生，从而重建 LT-HSC 和造血功能的机制：2) 评估先前存在的造血细胞的相对贡献CXCR4+内皮细胞与移植的CXCR4+VEGFR1+造血细胞进行血运重建缺血肢体；3) 评估血管生成因子强制表达在加速 BM SEC 再生和造血重建中的生理意义。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（包括再生障碍性贫血、骨髓增生异常综合征）提供新策略，并加速化疗、放疗和移植后的 BM 重建。 公共健康相关性：我们假设骨髓的血管生态位是一个动态的细胞微环境，对于骨髓抑制后造血功能的维持和重建至关重要。通过释放VEGF-A、PlGF、SDF-1和FGF-2等血管生成因子来再生CXCR4+VEGFR1+造血细胞，支持窦内皮细胞再生为功能性血管微环境，从而加速造血干细胞的恢复和造血功能的重建。我们预计，了解血管生成因子调节骨髓血管生态位重建的机制将为治疗造血衰竭状态（包括再生障碍性贫血、骨髓增生异常综合征）提供新策略，并加速化疗、放疗和骨髓移植后的骨髓重建。

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