Homogeneous and organized differentiation within embryoid bodies induced by microsphere-mediated delivery of small molecules.
Homogeneous and organized differentiation within embryoid bodies induced by microsphere-mediated delivery of small molecules.
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DOI：
10.1016/j.biomaterials.2009.01.007
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发表时间：
2009-05
期刊：
影响因子：
14
通讯作者：
McDevitt, Todd C.
中科院分区：
文献类型：
--
作者：
Carpenedo, Richard L.;Bratt-Leal, Andrs M.;Marklein, Ross A.;Seaman, Scott A.;Bowen, Nathan J.;McDonald, John F.;McDevitt, Todd C.
胚胎发育过程中的细胞特化和组织形成是由形态发生因子的局部浓度和时间表达精确控制的。类似地，多能胚胎干细胞可以在体外被诱导分化成响应于形态发生剂处理的特定表型。胚胎干细胞（ESC）通常分化为称为胚状体（EB）的3D球状体;然而，EB内的细胞分化通常是异质和无序的。在这项研究中，我们证明，在相反的可溶性形态发生剂治疗，交付的形态发生因子直接在EB微环境中的时空控制的方式使用聚合物微球产生均匀，同步和有组织的ESC分化。将释放视黄酸的可降解PLGA微球直接掺入EB中，并诱导形成囊状球状体，其独特地类似于早期条纹小鼠胚胎（E6.75）的表型和结构，FOXA 2+内脏内胚层的外部包裹OCT 4+细胞的上胚层样层。这些结果表明，使用可降解微球控制形态发生蛋白呈递给干细胞比简单的可溶性递送方法更有效地指导细胞分化和组织形成，并提出了一种独特的途径来研究形态发生因子对体外胚胎发育过程的时空影响。
Cell specification and tissue formation during embryonic development are precisely controlled by the local concentration and temporal presentation of morphogenic factors. Similarly, pluripotent embryonic stem cells can be induced to differentiate in vitro into specific phenotypes in response to morphogen treatment. Embryonic stem cells (ESCs) are commonly differentiated as 3D spheroids referred to as embryoid bodies (EBs); however, differentiation of cells within EBs is typically heterogeneous and disordered. In this study, we demonstrate that in contrast to soluble morphogen treatment, delivery of morphogenic factors directly within EB microenvironments in a spatiotemporally controlled manner using polymer microspheres yields homogeneous, synchronous and organized ESC differentiation. Degradable PLGA microspheres releasing retinoic acid were incorporated directly within EBs and induced the formation of cystic spheroids uniquely resembling the phenotype and structure of early streak mouse embryos (E6.75), with an exterior of FOXA2+ visceral endoderm enveloping an epiblast-like layer of OCT4+ cells. These results demonstrate that controlled morphogen presentation to stem cells using degradable microspheres more efficiently directs cell differentiation and tissue formation than simple soluble delivery methods and presents a unique route to study the spatiotemporal effects of morphogenic factors on embryonic developmental processes in vitro.
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