Human macrophage immunophenotype modulated by biomaterial-encapsulated MSC

描述(申请人提供)：成人组织来源的间充质基质细胞(MSC)在治疗包括心肌梗死、移植物抗宿主病和其他组织损伤(如难治性伤口)方面显示出良好的前景。目前在基于MSC的治疗方面的大部分工作包括开发细胞包埋基质来控制细胞植入后的功能和命运。虽然MSC已被证明具有免疫调节特性，但MSC包裹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，包裹在三维生物材料中的成人人骨髓间充质干细胞(BM-MSC)将优先调节宿主初级巨噬细胞的极化，从促炎状态转向促愈合和抗炎表型。为了在基于细胞的再生医学中开发有效的MSC水凝胶策略，需要清楚地了解包裹的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向相互作用。为实现这一目标，我们将：(1)制备具有良好生物力学性能的生物材料，包括强度和缺乏收缩的商业可获得的细胞输送基质用于BM-MSC包埋；(2)在三维共培养中评估生物材料包裹的BM-MSC调节血源性原代巨噬细胞的免疫表型；(3)确认三维生物材料包裹的BM-MSC在创伤模型中招募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.