Human macrophage immunophenotype modulated by biomaterial-encapsulated MSC

描述（由申请人提供）：成人组织来源的间充质基质细胞（MSC）已被证明有望治疗各种病理，包括心肌梗死、移植物抗宿主病和其他组织损伤，如难治性伤口。目前关于基于MSC的疗法的大部分工作包括细胞包埋基质的开发，以控制植入后的细胞功能和命运。虽然MSC已显示具有免疫调节特性，但MSC包封的生物基质对宿主巨噬细胞免疫表型和宿主异物反应的影响尚不清楚。我们假设包封到3-D生物材料中的成人、人骨髓来源的MSC（BM-MSC）将优先调节宿主原代巨噬细胞从促炎状态向促愈合和抗炎表型的极化。在基于细胞的再生医学中，开发有效的MSC-水凝胶策略需要清楚地了解封装的MSC、巨噬细胞和使用原代人类细胞的生物材料之间的这种三方相互作用。为此，我们将：（1）配制具有改善的生物力学性质的良好表征的生物材料，所述生物力学性质包括强度和相对于商业上可获得的用于BM-MSC包封的细胞递送基质缺乏收缩;（2）评估在3-D共培养物中由生物材料包埋的BM-MSC调节的血液来源的原代巨噬细胞的免疫表型;（3）证实3-D生物材料包埋的BM-MSC在伤口模型中募集和调节巨噬细胞促愈合表型的能力。

DESCRIPTION (provided by applicant): Adult tissue-derived mesenchymal stromal cells (MSC) have demonstrated promise in treating various pathologies including myocardial infarction, graft versus host disease and other tissue injuries such refractory wounds. Much of current work on MSC-based therapies consists of the development of cell entrapment matrix to control cell function and fate after implantation. While MSC had shown to have immunomodulatory properties, the impact of the MSC-encapsulated biomatrix on the host macrophage immunophenotype and host foreign body reaction is less clear. We hypothesize that adult, human bone marrow-derived MSC (BM- MSC) that are encapsulated into a 3-D biomaterial will preferentially modulate the polarization of host primary macrophages from a pro-inflammatory state towards a pro-healing and anti-inflammatory phenotype. A clear understanding of this three-way interaction between encapsulated MSC, macrophages, and biomaterial using primary human cells is required for the development of effective MSC-hydrogel strategies in cell-based regenerative medicine. To achieve this, we will: (1) formulate well-characterized biomaterials with improved biomechanic properties including strength and lack of contraction over commercially-available cell-delivery matrices for BM-MSC encapsulation; (2) assess the immunophenotype of blood-derived primary macrophages as modulated by biomaterial-entrapped BM-MSC in 3-D co-cultures; (3) confirm the ability of 3-D biomaterial- entrapped BM-MSC to recruit and modulate macrophage pro-healing phenotype in a wound model.