Marrow-inspired matrix cues rapidly affect early fate decisions of hematopoietic stem and progenitor cells.
Marrow-inspired matrix cues rapidly affect early fate decisions of hematopoietic stem and progenitor cells.
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DOI：
10.1126/sciadv.1600455
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发表时间：
2017-01
期刊：
影响因子：
13.6
通讯作者：
Harley BA
中科院分区：
文献类型：
--
作者：
Choi JS;Harley BA
原代鼠HSC表现出不同的命运决定与生物材料的参与，并由于骨髓启发的生物物理线索。造血是造血干细胞（HSC）在称为小生境的骨髓的独特区域内持续产生血液和免疫细胞的身体补体的生理过程。尽管先前的研究已经揭示了骨髓中细胞和细胞外基质（ECM）含量的梯度，并且基质弹性和配体类型被认为是干细胞命运的强调节剂，但对生物物理信号对HSC响应的影响知之甚少。使用骨髓启发ECM配体包被的聚丙烯酰胺基板，目前定义的刚度和基质配体线索，我们证明，整合素的参与和肌球蛋白II激活过程之间的相互作用影响的形态，增殖和骨髓谱系规范的原代小鼠HSC在24小时内离体。值得注意的是，离散的生物物理信号对HSC命运决定的影响似乎与已知的骨髓微环境转变相关。纤连蛋白和骨髓基质相关硬度的组合足以维持造血祖细胞群体，而胶原蛋白和层粘连蛋白分别增强增殖和骨髓分化。通过特异性整合素（α5β1和α v β3）抑制肌球蛋白II介导的收缩或与纤连蛋白的粘附，选择性地消除了基质环境对HSC命运决定的影响。总之，这些发现表明，粘附相互作用和基质生物物理特性是开发生物材料以指导HSC体外行为的关键设计考虑因素。
Primary murine HSCs show divergent fate decisions with biomaterial engagement and due to marrow-inspired biophysical cues. Hematopoiesis is the physiological process where hematopoietic stem cells (HSCs) continuously generate the body’s complement of blood and immune cells within unique regions of the bone marrow termed niches. Although previous investigations have revealed gradients in cellular and extracellular matrix (ECM) content across the marrow, and matrix elasticity and ligand type are believed to be strong regulators of stem cell fate, the impact of biophysical signals on HSC response is poorly understood. Using marrow-inspired ECM ligand–coated polyacrylamide substrates that present defined stiffness and matrix ligand cues, we demonstrate that the interplay between integrin engagement and myosin II activation processes affects the morphology, proliferation, and myeloid lineage specification of primary murine HSCs within 24 hours ex vivo. Notably, the impact of discrete biophysical signals on HSC fate decisions appears to be correlated to known microenvironmental transitions across the marrow. The combination of fibronectin and marrow matrix-associated stiffness was sufficient to maintain hematopoietic progenitor populations, whereas collagen and laminin enhanced proliferation and myeloid differentiation, respectively. Inhibiting myosin II–mediated contraction or adhesion to fibronectin via specific integrins (α5β1 and ανβ3) selectively abrogated the impact of the matrix environment on HSC fate decisions. Together, these findings indicate that adhesive interactions and matrix biophysical properties are critical design considerations in the development of biomaterials to direct HSC behavior in vitro.
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影响因子：
1.4
作者：
Choi JS;Harley BA
通讯作者：
Harley BA
影响因子：
4
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0903269107
发表时间：
2010-03-16
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
46.9
作者：
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通讯作者：
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