Human macrophage immunophenotype modulated by biomaterial-encapsulated MSC

描述（由申请人提供）：成体组织源性间充质间质细胞（MSC）在治疗各种疾病，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）方面显示出前景。目前基于间充质干细胞的治疗方法主要是开发细胞包裹基质来控制细胞植入后的功能和命运。虽然MSC已显示出免疫调节特性，但MSC包膜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，被封装成三维生物材料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的极化，从促炎状态转向促愈合和抗炎表型。为了在细胞再生医学中开发有效的MSC-水凝胶策略，需要清楚地了解被封装的MSC、巨噬细胞和使用原代人细胞的生物材料之间的这种三方相互作用。为了实现这一目标，我们将：(1)制定具有良好特征的生物材料，具有改进的生物力学性能，包括强度和缺乏收缩，超过商业上可用的细胞递送基质，用于BM-MSC封装；(2)在三维共培养中评估生物材料包埋的BM-MSC对血源性原代巨噬细胞的免疫表型的调节；(3)在伤口模型中证实三维生物材料包裹的BM-MSC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.