Rosenthal Adam, Macdonald Alice, Voldman Joel
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Biomaterials. 2007 Jul;28(21):3208-16. doi: 10.1016/j.biomaterials.2007.03.023. Epub 2007 Mar 27.
Cell-cell signaling is an important component of the stem cell microenvironment, affecting both differentiation and self-renewal. However, traditional cell-culture techniques do not provide precise control over cell-cell interactions, while existing cell-patterning technologies are limited when used with proliferating or motile cells. To address these limitations, we created the Bio Flip Chip (BFC), a microfabricated polymer chip containing thousands of microwells, each sized to trap down to a single stem cell. We have demonstrated the functionality of the BFC by patterning a 50 x 50 grid of murine embryonic stem cells (mESCs), with patterning efficiencies >75%, onto a variety of substrates--a cell-culture dish patterned with gelatin, a 3-D substrate, and even another layer of cells. We also used the BFC to pattern small groups of cells, with and without cell-cell contact, allowing incremental and independent control of contact-mediated signaling. We present quantitative evidence that cell-cell contact plays an important role in depressing mESC colony formation, and show that E-cadherin is involved in this negative regulatory pathway. Thus, by allowing exquisite control of the cellular microenvironment, we provide a technology that enables new applications in tissue engineering and regenerative medicine.
细胞间信号传导是干细胞微环境的重要组成部分,影响细胞分化和自我更新。然而,传统的细胞培养技术无法精确控制细胞间的相互作用,而现有的细胞图案化技术在用于增殖或运动细胞时存在局限性。为了解决这些限制,我们创建了生物翻转芯片(BFC),这是一种微加工的聚合物芯片,包含数千个微孔,每个微孔的大小都能捕获单个干细胞。我们通过将50×50网格的小鼠胚胎干细胞(mESC)以大于75%的图案化效率图案化到各种底物上,证明了BFC的功能,这些底物包括用明胶图案化的细胞培养皿、三维底物,甚至另一层细胞。我们还使用BFC对有或没有细胞间接触的小细胞群进行图案化,从而实现对接触介导信号传导的逐步和独立控制。我们提供了定量证据,证明细胞间接触在抑制mESC集落形成中起重要作用,并表明E-钙黏蛋白参与了这一负调控途径。因此,通过对细胞微环境进行精确控制,我们提供了一种能够在组织工程和再生医学中实现新应用的技术。