Bone Marrow Mesenchymal Stromal Cells Isolated From Multiple Sclerosis Patients Have Distinct Gene Expression Profile and Decreased Suppressive Function Compared With Healthy Counterparts
Bone Marrow Mesenchymal Stromal Cells Isolated From Multiple Sclerosis Patients Have Distinct Gene Expression Profile and Decreased Suppressive Function Compared With Healthy Counterparts
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DOI：
10.3727/096368913x675142
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发表时间：
2015-01-01
影响因子：
3.3
通讯作者：
Mamegrim, Kelen C. R.
中科院分区：
文献类型：
--
作者：
de Oliveira, Gislane L. V.;de Lima, Kalil W. A.;Mamegrim, Kelen C. R.
多发性硬化（MS）是中枢神经系统的慢性炎性自身免疫性疾病，由于针对髓鞘蛋白的免疫反应。多能间充质基质细胞（MSC）具有免疫抑制作用，已被用于治疗自身免疫性疾病。在我们的研究中，基因表达谱和体外免疫调节功能测试被用来比较骨髓来源的骨髓间充质干细胞从MS患者，在前和后自体造血干细胞移植（AHSCT）与健康供体。患者MSC相对地表现出i）在培养中的衰老; ii）相似的成骨和成脂分化潜能; iii）CD 105、CD 73、CD 44和HLA-A/B/C分子的表达降低; iv）与对照MSC相比，在AHSCT前的不同转录，产生618个差异表达的基因，包括TGFBI和HGF基因的下调以及FGF和HGF信号传导途径的调节; v）当AHSCT前MSC与同种异体T淋巴细胞共培养时，抗增殖作用降低; vi）两种共培养物（AHSCT前和AHSCT后MSC）的上清液中IL-10和TGF-β的分泌减少;和vii）MSC共培养后回收的调节细胞的百分比相似。移植后6个月分离的患者MSC的转录谱比来自健康MSC的转录谱更接近AHSCT前样品。考虑到患者间充质干细胞表现出表型变化，不同的转录谱和功能缺陷牵连MSC的免疫调节和免疫抑制活性，我们建议进一步MS临床研究应使用同种异体骨髓间充质干细胞来源于健康供体。我们还证明了用AHSCT治疗MS患者不会逆转在患者MSC中观察到的转录和功能改变。
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system, due to an immune reaction against myelin proteins. Multipotent mesenchymal stromal cells (MSCs) present immunosuppressive effects and have been used for the treatment of autoimmune diseases. In our study, gene expression profile and in vitro immunomodulatory function tests were used to compare bone marrow-derived MSCs obtained from MS patients, at pre- and postautologous hematopoietic stem cell transplantation (AHSCT) with those from healthy donors. Patient MSCs comparatively exhibited i) senescence in culture; ii) similar osteogenic and adipogenic differentiation potential; iii) decreased expression of CD 105, CD73, CD44, and HLA-A/B/C molecules; iv) distinct transcription at pre-AHSCT compared with control MSCs, yielding 618 differentially expressed genes, including the downregulation of TGFBI and HGF genes and modulation of the FGF and HGF signaling pathways; v) reduced antiproliferative effects when pre-AHSCT MSCs were cocultured with allogeneic T-lymphocytes; vi) decreased secretion of IL-10 and TGF-beta in supernatants of both cocultures (pre- and post-AHSCT MSCs); and vii) similar percentages of regulatory cells recovered after MSC cocultures. The transcriptional profile of patient MSCs isolated 6 months posttransplantation was closer to pre-AHSCT samples than from healthy MSCs. Considering that patient MSCs exhibited phenotypic changes, distinct transcriptional profile and functional defects implicated in MSC immunomodulatory and immunosuppressive activity, we suggest that further MS clinical studies should be conducted using allogeneic bone marrow MSCs derived from healthy donors. We also demonstrated that treatment of MS patients with AHSCT does not reverse the transcriptional and functional alterations observed in patient MSCs.