Immune modulation via adipose derived Mesenchymal Stem cells is driven by donor sex in vitro.
Immune modulation via adipose derived Mesenchymal Stem cells is driven by donor sex in vitro.
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DOI：
10.1038/s41598-021-91870-4
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发表时间：
2021-06-14
影响因子：
4.6
通讯作者：
McCracken S
中科院分区：
文献类型：
--
作者：
Mckinnirey F;Herbert B;Vesey G;McCracken S
间充质基质/干细胞（MSC）目前正在临床试验中使用，作为大范围遗传，免疫，骨科，心血管，内分泌和神经系统疾病的拟议治疗。间充质干细胞是有效的抗炎介质，被认为是免疫逃避，并采用大量的分泌囊泡沟通和修复受损组织。尽管其在治疗中大量使用，但很少将性别特异性作用机制视为使用的潜在混杂因素。本研究的目的是检查女性和男性脂肪来源的MSC的效力和功能，以进一步了解供体选择。方法将MSC扩增至第4代，收获分泌蛋白，-80 ℃保存。为了评估效力，还引发MSC并通过功能性免疫测定、ELISA、多重和免疫表型分析进行评估。结果女性MSC（fMSC）持续抑制外周血单个核细胞（PBMC）增殖，显著（p < 0.0001）高于男性MSC（mMSC）。在共培养mPBMC中，fMSC显示60.7 ± 15.6%的抑制，而mMSC显示22.5 ± 13.6%的抑制。类似地，fPBMC被fMSC抑制67.9 ± 10.4%，而mMSC抑制29.4 ± 9.3%。fMSC的增强的免疫抑制归因于产生更高浓度的抗炎介质，例如IDO 1（3301 pg/mL vs 1699 pg/mL）和可能的其他介质，包括IL-1 RA（1025 pg/mL vs 701 pg/mL）、PGE-2（6142 pg/mL vs 2448 pg/mL）以及相对于mMSC活化后VCAM-1的延长表达。相比之下，mMSC比fMSC产生更多的炎性G-CSF（806 pg/mL vs 503 pg/mL）。此外，IDO 1表达与免疫抑制和fMSC相关，但与mMSC诱导的IL-2受体下调和早期T细胞活化标记物CD 69在PBMCs中的持续表达无关，进一步强调了性别之间免疫调节潜力的差异。结论体外培养的雌性MSC比雄性MSC具有更强的增殖能力。雄性MSC不能匹配雌性MSC驱动的免疫调节和利用炎症微环境对其有利是明显的，并且当使用同种异体雄性MSC作为疾病状态的治疗剂时可能是危险信号。
Mesenchymal stromal/stem cells (MSCs) are currently being used in clinical trials as proposed treatments for a large range of genetic, immunological, orthopaedic, cardiovascular, endocrine and neurological disorders. MSCs are potent anti-inflammatory mediators which are considered immune evasive and employ a large range of secreted vesicles to communicate and repair damaged tissue. Despite their prolific use in therapy, sex specific mechanism of action is rarely considered as a potential confounding factor for use. The purpose of this study was to examine the potency and functionality of both female and male adipose derived MSCs in order to gain further insights into donor selection. Methods MSC were expanded to passage 4, secretome was harvested and stored at − 80c. To assess potency MSC were also primed and assessed via functional immune assays, ELISA, multiplex and immunophenotyping. Results Female MSCs (fMSC), consistently suppressed Peripheral blood mononuclear cell (PBMC) proliferation significantly (p < 0.0001) more than male MSC (mMSC). In co-culture mPBMCs, showed 60.7 ± 15.6% suppression with fMSCs compared with 22.5 ± 13.6% suppression with mMSCs. Similarly, fPBMCs were suppressed by 67.9 ± 10.4% with fMSCs compared to 29.4 ± 9.3% with mMSCs. The enhanced immunosuppression of fMSCs was attributed to the production of higher concentrations of the anti-inflammatory mediators such as IDO1 (3301 pg/mL vs 1699 pg/mL) and perhaps others including IL-1RA (1025 pg/mL vs 701 pg/mL), PGE-2 (6142 pg/mL vs 2448 pg/mL) and prolonged expression of VCAM-1 post activation relative to mMSCs. In contrast, mMSCs produces more inflammatory G-CSF than fMSCs (806 pg/mL vs 503 pg/mL). Moreover, IDO1 expression was correlated to immune suppression and fMSCs, but not mMSCs induced downregulation of the IL-2 receptor and sustained expression of the early T cell activation marker, CD69 in PBMCs further highlighting the differences in immunomodulation potentials between the sexes. Conclusion In conclusion, our data shows that female MSC are more potent in vitro than their male counterparts. The inability of male MSC to match female MSC driven immunomodulation and to use the inflammatory microenvironment to their advantage is evident and is likely a red flag when using allogeneic male MSC as a therapeutic for disease states.
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