Jha Amit K, Tharp Kevin M, Ye Jianqin, Santiago-Ortiz Jorge L, Jackson Wesley M, Stahl Andreas, Schaffer David V, Yeghiazarians Yerem, Healy Kevin E
Department of Bioengineering, University of California, Berkeley, CA 94720, USA; Department of Material Science and Engineering, University of California, Berkeley, CA 94720, USA.
Department of Nutritional Science and Toxicology, University of California, Berkeley, CA 94720, USA.
Biomaterials. 2015 Apr;47:1-12. doi: 10.1016/j.biomaterials.2014.12.043. Epub 2015 Jan 22.
We have generated a bioinspired tunable system of hyaluronic acid (HyA)-based hydrogels for Matrix-Assisted Cell Transplantation (MACT). With this material, we have independently evaluated matrix parameters such as adhesion peptide density, mechanical properties, and growth factor sequestering capacity, to engineer an environment that imbues donor cells with a milieu that promotes survival and engraftment with host tissues after transplantation. Using a versatile population of Sca-1(+)/CD45(-) cardiac progenitor cells (CPCs), we demonstrated that the addition of heparin in the HyA hydrogels was necessary to coordinate the presentation of TGFβ1 and to support the trophic functions of the CPCs via endothelial cell differentiation and vascular like tubular network formation. Presentation of exogenous TGFβ1 by binding with heparin improved differentiated CPC function by sequestering additional endogenously-produced angiogenic factors. Finally, we demonstrated that TGFβ1 and heparin-containing HyA hydrogels can promote CPC survival when implanted subcutaneously into murine hind-limbs and encouraged their participation in the ensuing neovascular response, which included blood vessels that had anastomosed with the host's blood vessels.
我们构建了一种受生物启发的基于透明质酸（HyA）的水凝胶可调系统，用于基质辅助细胞移植（MACT）。利用这种材料，我们独立评估了诸如黏附肽密度、机械性能和生长因子螯合能力等基质参数，以构建一个能为供体细胞提供促进移植后存活并与宿主组织整合的环境。使用多能性的Sca-1(+)/CD45(-)心脏祖细胞（CPCs），我们证明在HyA水凝胶中添加肝素对于协调TGFβ1的呈现以及通过内皮细胞分化和血管样管状网络形成来支持CPCs的营养功能是必要的。通过与肝素结合呈现外源性TGFβ1，通过螯合额外的内源性产生的血管生成因子改善了分化的CPC功能。最后，我们证明当将含TGFβ1和肝素的HyA水凝胶皮下植入小鼠后肢时，可促进CPC存活，并促使它们参与随后的新生血管反应，其中包括与宿主血管吻合的血管。
