A novel role of CD73-IFNγ signalling axis in human mesenchymal stromal cell mediated inflammatory macrophage suppression

IF 3.4 3区 环境科学与生态学 Q3 CELL & TISSUE ENGINEERING Regenerative Therapy Pub Date : 2024-06-01 DOI:10.1016/j.reth.2024.05.011
Shashank Chandanala, Govind Mohan, David-Luther Manukonda, Anujith Kumar, Jyothi Prasanna
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Abstract

Introduction

Immunomodulation is the predominant mechanism via which Mesenchymal stromal cells (MSCs) mediate their therapeutic benefits. However, inconsistent success in numerous clinical trials warrants a better understating of the molecular mechanisms regulating their immunomodulatory properties. CD73, an ecto-5′-nucleotidase is abundantly expressed by MSCs, however its precise role in regulating their immunomodulatory properties is still elusive. The present study explored the role of CD73 in Interferon-gamma (IFNγ) sensing and in turn their ability to suppress “inflammatory” M1 macrophages.

Materials and methods

CD73 knockdown MSCs (CD73-KDN) were initially assessed for expression of immunoregulatory molecules and IFNγ sensing ability by analysing expression of IFNγ signalling downstream targets such as pSTAT-1, Interferon-Stimulated Genes (ISG) and Indoleamine 2,3-dioxygnease (IDO), a prototypic IFNγ-induced immunomodulator. Next CD73-KDN MSCs were co-cultured with inflammatory M1 macrophages and evaluated for their ability to suppress them. To delineate the contributory role of CD73 and IFNγ signalling downstream target IDO, they were overexpressed independently in CD73-KDN MSCs and re-evaluated for their ability to suppress M1 macrophages.

Results

CD73-KDN MSCs exhibited reduced expression of immunoregulatory molecules and were refractory to IFNγ signalling as indicated by attenuated expression of pSTAT-1, Interferon-Stimulated Genes (ISG) and Indoleamine 2,3-dioxygnease (IDO) upon IFNγ exposure. Since sensing of inflammation is critical for MSC mediated immunomodulation, CD73-KDN MSCs were functionally evaluated for their ability to immune-modulate “inflammatory” M1 macrophages wherein they failed to suppress M1 macrophages. Interestingly, ectopic expression of either CD73 or IFNγ signalling target IDO1 in CD73-KDN MSCs restored their ability to suppress M1 macrophages, establishing the importance of CD73-IFNγ signalling axis in MSC-mediated inflammatory macrophage suppression.

Conclusion

The present study uncovers the unexplored role of CD73-IFNγ axis in MSC-mediated M1 macrophage suppression. MSC-educated macrophages are the actual immune-modulators at MSC transplant sites, thus CD73 can serve as a key immune-potency marker for benchmarking therapeutically relevant MSCs.

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CD73-IFNγ 信号轴在人类间充质基质细胞介导的炎性巨噬细胞抑制中的新作用
导言免疫调节是间充质干细胞(MSCs)发挥治疗作用的主要机制。然而,在众多临床试验中取得的成功并不一致,因此需要更好地了解调控间充质干细胞免疫调节特性的分子机制。CD73是一种外向5′-核苷酸酶,在间充质干细胞中大量表达,但其在调节间充质干细胞免疫调节特性中的确切作用仍未确定。本研究探讨了 CD73 在干扰素-γ(IFNγ)感应中的作用,以及其反过来抑制 "炎症性 "M1 巨噬细胞的能力。材料与方法CD73基因敲除间充质干细胞(CD73-KDN)首先通过分析IFNγ信号下游靶标(如pSTAT-1、干扰素刺激基因(ISG)和吲哚胺-2,3-二氧基内酯酶(IDO),一种IFNγ诱导的原型免疫调节剂)的表达来评估免疫调节分子的表达和IFNγ感应能力。接下来,CD73-KDN 间充质干细胞与炎性 M1 巨噬细胞共同培养,并评估其抑制巨噬细胞的能力。为了明确 CD73 和 IFNγ 信号下游靶点 IDO 的作用,我们在 CD73-KDN 间充质干细胞中独立地过表达了这两种信号,并重新评估了它们抑制 M1 巨噬细胞的能力。结果CD73-KDN间充质干细胞的免疫调节分子表达量减少,并且对IFNγ信号具有耐受性,这表现在IFNγ暴露时pSTAT-1、干扰素刺激基因(ISG)和吲哚胺-2,3-二氧化酶(IDO)的表达量减少。由于对炎症的感知对于间充质干细胞介导的免疫调节至关重要,因此对 CD73-KDN 间充质干细胞进行了功能评估,以确定它们对 "炎症性 "M1 巨噬细胞进行免疫调节的能力,结果发现它们未能抑制 M1 巨噬细胞。有趣的是,在 CD73-KDN 间充质干细胞中异位表达 CD73 或 IFNγ 信号靶 IDO1 可恢复其抑制 M1 巨噬细胞的能力,从而确定了 CD73-IFNγ 信号轴在间充质干细胞介导的炎性巨噬细胞抑制中的重要性。间充质干细胞教育的巨噬细胞是间充质干细胞移植部位的实际免疫调节剂,因此CD73可作为治疗相关间充质干细胞的关键免疫能力标志物。
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来源期刊
Regenerative Therapy
Regenerative Therapy Engineering-Biomedical Engineering
CiteScore
6.00
自引率
2.30%
发文量
106
审稿时长
49 days
期刊介绍: Regenerative Therapy is the official peer-reviewed online journal of the Japanese Society for Regenerative Medicine. Regenerative Therapy is a multidisciplinary journal that publishes original articles and reviews of basic research, clinical translation, industrial development, and regulatory issues focusing on stem cell biology, tissue engineering, and regenerative medicine.
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