Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India.
Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, New Delhi, 110029, India.
Stem Cell Res Ther. 2024 Oct 29;15(1):381. doi: 10.1186/s13287-024-03947-2.
Mesenchymal stem cells (MSCs) have emerged as promising candidates for immune modulation in various diseases that are associated with dysregulated immune responses like Graft-versus-Host-Disease (GVHD). MSCs are pleiotropic and the fate of MSCs following administration is a major determinant of their therapeutic efficacy.
Human MSCs were derived from bone marrow (BM) and Wharton's Jelly (WJ) and preconditioned through exposure to hypoxia and induction of apoptosis, either sequentially or simultaneously. The immune programming potential of preconditioned MSCs was evaluated by assessing their effects on T cell proliferation, induction of Tregs, programming of effector T-cell towards Th2 phenotype, macrophage polarization in the direct co-culture of MSCs and aGVHD patients-derived PBMNCs. Additionally, efferocytosis of MSCs and relative change in the expression of immunomodulatory soluble factors were examined.
Our study demonstrated that hypoxia preconditioned apoptotic MSCs (BM-MSCs, WJ-MSCs) bear more immune programming ability in a cellular model of acute Graft-versus-Host-Disease (aGVHD). Our findings revealed that WJ-MSCs were superior to BM-MSCs for immune regulation. These induced the differentiation of CD4T-cell into Tregs, enhanced Th2 effector responses, and simultaneously mitigated Th1- and Th17 responses. Additionally, this approach led to the polarization of M1 macrophages toward an M2 phenotype.
Our study highlights the potential of WJ-MSCs conditioned with hypoxia and apoptosis concurrently, as a promising therapeutic strategy for aGVHD. It underscores the importance of considering MSC apoptosis in optimizing MSCs-based cellular therapy protocols for enhanced therapeutic efficacy in aGvHD.
间充质干细胞（MSCs）已成为各种疾病免疫调节的有前途的候选物，这些疾病与免疫反应失调有关，如移植物抗宿主病（GVHD）。MSCs 具有多能性，并且给药后 MSCs 的命运是其治疗效果的主要决定因素。
人 MSCs 源自骨髓（BM）和沃顿氏胶（WJ），并通过暴露于缺氧和诱导细胞凋亡来预处理，无论是顺序还是同时进行。通过评估预处理 MSC 对 T 细胞增殖、诱导 Tregs、将效应 T 细胞编程为 Th2 表型、在 MSC 和 aGVHD 患者来源的 PBMNCs 的直接共培养中诱导巨噬细胞极化的作用，评估了预处理 MSC 的免疫编程潜力。此外，还检查了 MSC 的吞噬作用和免疫调节可溶性因子表达的相对变化。
我们的研究表明，缺氧预处理凋亡 MSC（BM-MSCs、WJ-MSCs）在急性移植物抗宿主病（aGVHD）的细胞模型中具有更强的免疫编程能力。我们的研究结果表明，WJ-MSCs 比 BM-MSCs 更适合免疫调节。它们诱导 CD4T 细胞分化为 Tregs，增强 Th2 效应反应，同时减轻 Th1 和 Th17 反应。此外，这种方法导致 M1 巨噬细胞向 M2 表型极化。
我们的研究强调了同时用缺氧和细胞凋亡预处理 WJ-MSCs 的潜力，作为 aGVHD 的一种有前途的治疗策略。它强调了在优化基于 MSC 的细胞治疗方案以提高 aGVHD 治疗效果时考虑 MSC 凋亡的重要性。
