Heart transplantation is the final life-saving therapeutic strategy for many end-stage heart diseases. Long-term immunosuppressive regimens are needed to prevent allograft rejection. Mesenchymal stromal cells (MSCs) have been shown as immunomodulatory therapy for organ transplantation. However, the effect of dose and timing of MSC treatment on heart transplantation has not yet been examined. In this study, we infused three doses (1 × 10⁶, 2 × 10⁶, or 5 × 10⁶ cells) of human MSCs (hMSCs) to the recipient BALB/c mice before (7 days or 24 h) or after (24 h) receiving C57BL/6 cardiac transplants. We found that infusion of high dose hMSCs (5 × 10⁶) at 24 h post-transplantation significantly prolonged the survival time of cardiac grafts. To delineate the underlying mechanism, grafts, spleens, and draining lymph nodes were harvested for analysis. Dose-dependent effect of hMSC treatment was shown in: (1) alleviation of International Society of Heart and Lung Transplantation (ISHLT) score in grafts; (2) reduction of the population of CD4⁺ and CD8⁺ T cells; (3) increase of regulatory T (Treg) cells; (4) and decrease of serum levels of inflammatory cytokines and donor-specific antibodies. Taken together, we showed timing critical and dose-dependent immunomodulatory effects of hMSC treatment against acute allograft rejection in a mouse model of heart transplantation.

中文翻译：

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人间充质基质细胞输注对小鼠心脏同种异体移植排斥的剂量和时间依赖性影响

心脏移植是许多终末期心脏病的最终挽救生命的治疗策略。需要长期免疫抑制方案来防止同种异体移植排斥。间充质基质细胞 (MSC) 已被证明可作为器官移植的免疫调节疗法。然而，MSC 治疗的剂量和时间对心脏移植的影响尚未得到研究。在本研究中，我们在（7 天或 24 小时）之前（7 天或 24 小时）向受体 BALB/c 小鼠注射了三种剂量（1 × 10 ⁶、2 × 10 ⁶或 5 × 10 ⁶细胞）的人 MSC（hMSC）（ 24 小时）接受 C57BL/6 心脏移植。我们发现输注高剂量 hMSCs (5 × 10 ⁶) 移植后 24 小时显着延长心脏移植物的存活时间。为了描述潜在的机制，收集了移植物、脾脏和引流淋巴结进行分析。hMSC 治疗的剂量依赖性效应显示在：(1) 国际心肺移植学会 (ISHLT) 移植物评分的缓解；(2) CD4 ⁺和CD8 ⁺ T细胞数量减少；(3)调节性T(Treg)细胞增多；(4)血清炎性细胞因子和供体特异性抗体水平降低。总之，我们在心脏移植小鼠模型中显示了 hMSC 治疗对急性同种异体移植排斥反应的时间关键性和剂量依赖性免疫调节作用。