Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
J Cell Physiol. 2022 Jul;237(7):3001-3011. doi: 10.1002/jcp.30756. Epub 2022 May 6.
The breakdown of gastrointestinal tract immune homeostasis leads to Crohn's disease (CD). Mesenchymal stem cells (MSCs) have demonstrated clinical efficacy in treating CD in clinical trials, but there is little known about the mechanism of healing. Considering the critical roles of macrophage polarization in CD and immunomodulatory properties of MSCs, we sought to decipher the interaction between adipose-derived MSCs and macrophages, including their cytokine production, regulation of differentiation, and pro-/anti-inflammatory function. RNA extraction and next generation sequencing was performed in adipose tissue from healthy control patients' mesentery (n = 3) and CD mesentery (n = 3). Infiltrated macrophage activation in the CD mesentery was tested, MSCs and extracellular vesicles (EVs) were isolated to compare the regulation of macrophage differentiation, cytokines production, and self-renewal capacities in vitro. CD patients' mesentery has increased M1 macrophage polarization and elevated activation. MSCs and their derived EVs, isolated from inflamed Crohn's mesentery, leads to a rapid differentiation of monocytes to a M1-like polarized phenotype. Conversely, MSCs and their derived EVs from healthy, non-Crohn's patients results in monocyte polarization into a M2 phenotype; this is seen regardless of the adipose source of MSCs (subcutaneous fat, omentum, normal mesentery). EVs derived from MSCs have the ability to regulate macrophage differentiation. Healthy MSCs and their associated EVs have the ability to drive monocytes to a M2 subset, effectively reversing an inflammatory phenotype. This mechanism supports why MSCs may be an effective therapeutic in CD and highlights EVs as a novel therapeutic for further exploration.
胃肠道免疫稳态的破坏导致了克罗恩病（CD）。间充质干细胞（MSCs）在临床试验中已被证明对 CD 具有临床疗效，但对其愈合机制知之甚少。鉴于巨噬细胞极化在 CD 中的关键作用和 MSCs 的免疫调节特性，我们试图阐明脂肪来源的 MSCs 与巨噬细胞之间的相互作用，包括它们的细胞因子产生、分化调节和促/抗炎功能。对来自健康对照患者肠系膜（n=3）和 CD 肠系膜（n=3）的脂肪组织进行 RNA 提取和下一代测序。测试了 CD 肠系膜中浸润的巨噬细胞激活情况，分离 MSCs 和细胞外囊泡（EVs），以比较体外巨噬细胞分化、细胞因子产生和自我更新能力的调节。CD 患者的肠系膜中 M1 巨噬细胞极化增加，激活增强。从炎症性克罗恩病肠系膜中分离的 MSCs 和其衍生的 EVs 可迅速将单核细胞分化为 M1 样极化表型。相反，来自健康、非克罗恩病患者的 MSCs 和其衍生的 EVs 导致单核细胞向 M2 表型极化；无论 MSCs 的脂肪来源（皮下脂肪、网膜、正常肠系膜）如何，都会出现这种情况。MSC 衍生的 EV 具有调节巨噬细胞分化的能力。健康的 MSCs 及其相关的 EV 具有将单核细胞驱动为 M2 亚群的能力，有效地逆转炎症表型。该机制支持为什么 MSCs 可能是 CD 的有效治疗方法，并强调 EV 是一种有前途的治疗方法，值得进一步探索。
