Inhibition of Endosteal Vascular Niche Remodeling Rescues Hematopoietic Stem Cell Loss in AML.
Inhibition of Endosteal Vascular Niche Remodeling Rescues Hematopoietic Stem Cell Loss in AML.
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DOI：
10.1016/j.stem.2017.11.006
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发表时间：
2018-01-04
期刊：
影响因子：
23.9
通讯作者：
Lo Celso C
中科院分区：
文献类型：
--
作者：
Duarte D;Hawkins ED;Akinduro O;Ang H;De Filippo K;Kong IY;Haltalli M;Ruivo N;Straszkowski L;Vervoort SJ;McLean C;Weber TS;Khorshed R;Pirillo C;Wei A;Ramasamy SK;Kusumbe AP;Duffy K;Adams RH;Purton LE;Carlin LM;Lo Celso C
骨髓血管壁龛维持造血干细胞（hsc），并在白血病中急剧重塑以支持病理功能。急性髓性白血病（AML）细胞产生血管生成因子，这可能有助于这种重塑，但抗血管生成疗法并不能改善AML患者的预后。通过活体显微镜，我们发现AML的进展导致骨髓中央和髓内区血管的不同重塑。AML内皮细胞产生促炎和抗血管生成细胞因子，并逐渐降解内皮细胞、基质细胞和成骨细胞，而中央骨髓保持血管化，脾血管龛扩张。重塑的内皮区支持非白血病造血干细胞的能力降低，这与正常造血功能的丧失有关。用小分子去铁胺或遗传方法保护内皮细胞可挽救造血干细胞的损失，促进化疗疗效，提高生存率。这些发现表明，防止髓内血管退化可能会改善目前治疗急性髓性白血病的范例。急性髓性白血病（AML）导致骨髓间质进行性重构HSC的损失与骨髓内重构存在时空相关性体内成像显示健康造血细胞的跨内皮迁移内皮内血管的拯救保存了HSC并增强了化疗的疗效急性髓性白血病骨髓内进展的多模态显微镜显示骨髓内血管的局灶性和进行性重构以及成骨细胞的损失。造血干细胞（HSC）和造血干细胞龛。保留内皮血管可增加造血干细胞的存活数量，提高化疗的疗效。
Bone marrow vascular niches sustain hematopoietic stem cells (HSCs) and are drastically remodeled in leukemia to support pathological functions. Acute myeloid leukemia (AML) cells produce angiogenic factors, which likely contribute to this remodeling, but anti-angiogenic therapies do not improve AML patient outcomes. Using intravital microscopy, we found that AML progression leads to differential remodeling of vasculature in central and endosteal bone marrow regions. Endosteal AML cells produce pro-inflammatory and anti-angiogenic cytokines and gradually degrade endosteal endothelium, stromal cells, and osteoblastic cells, whereas central marrow remains vascularized and splenic vascular niches expand. Remodeled endosteal regions have reduced capacity to support non-leukemic HSCs, correlating with loss of normal hematopoiesis. Preserving endosteal endothelium with the small molecule deferoxamine or a genetic approach rescues HSCs loss, promotes chemotherapeutic efficacy, and enhances survival. These findings suggest that preventing degradation of the endosteal vasculature may improve current paradigms for treating AML. AML leads to progressive remodeling of endosteal stroma HSC loss is spatiotemporally correlated with endosteal remodeling In vivo imaging reveals transendothelial migration of healthy hematopoietic cells Rescue of endosteal vessels preserves HSCs and enhances the efficacy of chemotherapy Multi-modal microscopy of acute myeloid leukemia progression within the bone marrow reveals focal and progressive remodeling of endosteal blood vessels coupled to loss of osteoblasts, hematopoietic stem cells (HSCs), and HSC niches. Preserving endosteal vessels increases the number of surviving HSCs and improves the efficacy of chemotherapy.
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影响因子：
64.8
作者：
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通讯作者：
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DOI：
10.1084/jem.182.6.2069
发表时间：
1995-12-01
期刊：
The Journal of experimental medicine
影响因子：
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作者：
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影响因子：
64.8
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影响因子：
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