Targeting stem cell niche can protect hematopoietic stem cells from chemotherapy and G-CSF treatment.
Targeting stem cell niche can protect hematopoietic stem cells from chemotherapy and G-CSF treatment.
复制标题
靶向干细胞生态位可以保护造血干细胞免受化疗和 G-CSF 治疗的影响
DOI：
10.1186/s13287-015-0164-4
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发表时间：
2015-09-15
影响因子：
7.5
通讯作者：
Qiu L
中科院分区：
文献类型：
--
作者：
Li S;Zou D;Li C;Meng H;Sui W;Feng S;Cheng T;Zhai Q;Qiu L
造血干/祖细胞（HSPCs）存在于一个被严格控制的局部微环境中，称为骨髓龛。专门的微环境或生态位不仅提供了一个良好的栖息地HSPC的维护和发展，但也管理干细胞function.MethodWe研究细胞毒性药物对骨髓生态位的影响。为了在临床环境中模拟多轮化疗后进行自体造血干细胞（HSC）移植，我们进一步验证了靶向小生境可能改善小鼠模型中基于干细胞的治疗的假设。结果我们发现，多轮细胞毒性药物治疗显著破坏了自体HSPCs移植患者的小生境，并且治疗后血清骨钙素水平显著降低（P= 0.01）。在小鼠模型中，多轮化疗和粒细胞集落刺激因子（G-CSF）治疗后，CD 45 − Ter 119 −OPN+成骨细胞的数量显著减少（P < 0.01）。甲状旁腺激素（PTH）或核因子κ-B受体激活剂配体（RANKL）治疗显著增加了动员到外周血（PB）中用于干细胞收获的HSC数量，并保护干细胞免于重复暴露于细胞毒性化疗。G-CSF和PTH处理组HSC保存率明显高于对照组（P < 0.05）。此外，受体小鼠移植与循环HSPCs，以前用PTH和RANKL治疗表现出强大的骨髓和淋巴细胞移植的小鼠相比，造血干细胞移植后化疗或G-CSF treatment.ConclusionThese数据提供了新的证据，小生境可能是一个重要的目标，以药物为基础的干细胞治疗。
IntroductionHematopoietic stem/progenitor cells (HSPCs) reside in a tightly controlled local microenvironment called bone marrow niche. The specialized microenvironment or niche not only provides a favorable habitat for HSPC maintenance and development but also governs stem cell function.MethodWe investigated the effect of cytotoxic drugs on bone marrow niche. To mimic the multiple rounds of chemotherapy followed by autologous hematopoietic stem cells (HSCs) transplantation in a clinical setting, we further verified the hypothesis that targeting the niche might improve stem cell–based therapies in mouse models.ResultsWe found that multiple rounds of cytotoxic drug treatment significantly disrupted niche and serum osteocalcin level was significantly reduced after treatment in autologous HSPCs transplanted patients (P= 0.01). In mouse models, the number of CD45−Ter119−OPN+osteoblasts was significantly reduced after multiple rounds of chemotherapies and granulocyte colony stimulating factor (G-CSF) treatment (P < 0.01). Parathyroid hormone (PTH) or receptor activator of nuclear factor kappa-B ligand (RANKL) treatment significantly increased the number of HSCs mobilized into peripheral blood (PB) for stem cell harvesting and protected stem cells from repeated exposure to cytotoxic chemotherapy. Treatments with G-CSF and PTH significantly increased the preservation of the HSC pool (P < 0.05). Moreover, recipient mice transplanted with circulation HSPCs that were previously treated with PTH and RANKL showed robust myeloid and lymphatic cell engraftment compared to the mice transplanted with HSCs after chemotherapy or G-CSF treatment.ConclusionThese data provide new evidence that the niche may be an important target for drug-based stem cell therapy.