Najar Mehdi, Merimi Makram, Faour Wissam H, Lombard Catherine A, Moussa Agha Douâa, Ouhaddi Yassine, Sokal Etienne M, Lagneaux Laurence, Fahmi Hassan
Laboratory of Clinical Cell Therapy, Jules Bordet Institute, Université Libre de Bruxelles, 1070 Brussels, Belgium.
Osteoarthritis Research Unit, Department of Medicine, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC H2X 0A9, Canada.
Pharmaceutics. 2021 Oct 19;13(10):1736. doi: 10.3390/pharmaceutics13101736.
Foreskin, considered a biological waste material, has been shown to be a reservoir of therapeutic cells. The immunomodulatory properties of mesenchymal stromal/stem cells (MSCs) from the foreskin (FSK-MSCs) are being evaluated in cell-based therapy for degenerative, inflammatory and autoimmune disorders. Within the injured/inflamed tissue, proinflammatory lymphocytes such as IL-17-producing T helper cells (Th17) may interact with the stromal microenvironment, including MSCs. In this context, MSCs may encounter different levels of T cells as well as specific inflammatory signals. Uncovering the cellular and molecular changes during this interplay is central for developing an efficient and safe immunotherapeutic tool. To this end, an in vitro human model of cocultures of FSK-MSCs and T cells was established. These cocultures were performed at different cell ratios in the presence of an inflammatory setting. After confirming that FSK-MSCs respond to ISCT criteria by showing a typical phenotype and multilineage potential, we evaluated by flow cytometry the expression of Th17 cell markers IL-17A, IL23 receptor and RORγt within the lymphocyte population. We also measured 15 human Th17 pathway-related cytokines. Regardless of the T cell/MSC ratio, we observed a significant increase in IL-17A expression associated with an increase in IL-23 receptor expression. Furthermore, we observed substantial modulation of IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, INF-γ, sCD40, and TNF-α secretion. These findings suggest that FSK-MSCs are receptive to their environment and modulate the T cell response accordingly. The changes within the secretome of the stromal and immune environment are likely relevant for the therapeutic effect of MSCs. FSK-MSCs represent a valuable cellular product for immunotherapeutic purposes that needs to be further clarified and developed.
包皮，曾被视为一种生物废弃物，现已证明它是治疗性细胞的储存库。来自包皮的间充质基质/干细胞（FSK-MSCs）的免疫调节特性正在针对退行性、炎症性和自身免疫性疾病的细胞疗法中进行评估。在受损/发炎组织内，促炎淋巴细胞，如产生白细胞介素-17的辅助性T细胞（Th17），可能会与包括MSCs在内的基质微环境相互作用。在此背景下，MSCs可能会遇到不同水平的T细胞以及特定的炎症信号。揭示这种相互作用过程中的细胞和分子变化对于开发一种高效且安全的免疫治疗工具至关重要。为此，建立了FSK-MSCs与T细胞共培养的体外人体模型。这些共培养在炎症环境下以不同的细胞比例进行。在确认FSK-MSCs通过显示典型表型和多向分化潜能符合国际细胞治疗协会（ISCT）标准后，我们通过流式细胞术评估淋巴细胞群体中Th17细胞标志物白细胞介素-17A、白细胞介素-23受体和维甲酸相关孤儿受体γt（RORγt）的表达。我们还检测了15种与人类Th17途径相关的细胞因子。无论T细胞/MSC比例如何，我们都观察到白细胞介素-17A表达显著增加，同时白细胞介素-23受体表达也增加。此外，我们观察到白细胞介素-1β、白细胞介素-4、白细胞介素-6、白细胞介素-10、白细胞介素-17A、白细胞介素-17F、白细胞介素-21、白细胞介素-22、白细胞介素-23、白细胞介素-25、白细胞介素-31、白细胞介素-33、干扰素-γ、可溶性细胞间黏附分子-40（sCD40）和肿瘤坏死因子-α（TNF-α）分泌受到显著调节。这些发现表明FSK-MSCs能够感知其环境并相应地调节T细胞反应。基质和免疫环境分泌组中的变化可能与MSCs的治疗效果相关。FSK-MSCs是一种有价值的用于免疫治疗目的的细胞产品，需要进一步阐明和开发。
