Stenger Elizabeth O, Chinnadurai Raghavan, Yuan Shala, Garcia Marco, Arafat Dalia, Gibson Greg, Krishnamurti Lakshmanan, Galipeau Jacques
Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia.
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
Biol Blood Marrow Transplant. 2017 May;23(5):736-745. doi: 10.1016/j.bbmt.2017.01.081. Epub 2017 Jan 26.
Hematopoietic cell transplantation (HCT) is the only cure for sickle cell disease (SCD), but engraftment remains challenging in patients lacking matched donors. Infusion of mesenchymal stromal cells (MSCs) at the time of HCT may promote hematopoiesis and ameliorate graft-versus-host disease. Experimental murine models suggest MSC major histocompatibility complex compatibility with recipient impacts their in vivo function, suggesting autologous MSCs could be superior to third-party MSCs for promoting HCT engraftment. Here we tested whether bone marrow (BM)-derived MSCs from SCD subjects have comparable functionality compared with MSCs from healthy volunteers. SCD MSC doubling time and surface marker phenotype did not differ significantly from non-SCD. Third-party and autologous (SCD) T cell proliferation was suppressed in a dose-dependent manner by all MSCs. SCD MSCs comparably expressed indoleamine-2,3-dioxygenase, which based on transwell and blocking experiments appeared to be the dominant immunomodulatory pathway. The expression of key genes involved in hematopoietic stem cell (HSC)-MSC interactions was minimally altered between SCD and non-SCD MSCs. Expression was, however, altered by IFN-γ stimulation, particularly CXCL14, CXCL26, CX3CL1, CKITL, and JAG1, indicating the potential to augment MSC expression by cytokine stimulation. These data demonstrate the feasibility of expanding BM-derived MSCs from SCD patients that phenotypically and functionally do not differ per International Society of Cell Therapy essential criteria from non-SCD MSCs, supporting initial evaluation (primarily for safety) of autologous MSCs to enhance haploidentical HSC engraftment in SCD.
造血细胞移植（HCT）是镰状细胞病（SCD）的唯一治愈方法，但对于缺乏匹配供体的患者而言，植入仍然具有挑战性。在HCT时输注间充质基质细胞（MSC）可能会促进造血并改善移植物抗宿主病。实验性小鼠模型表明，MSC与受体的主要组织相容性复合体兼容性会影响其体内功能，这表明自体MSC在促进HCT植入方面可能优于第三方MSC。在这里，我们测试了来自SCD受试者的骨髓（BM）源性MSC与健康志愿者的MSC相比是否具有可比的功能。SCD MSC的倍增时间和表面标志物表型与非SCD相比无显著差异。所有MSC均以剂量依赖性方式抑制第三方和自体（SCD）T细胞增殖。SCD MSC同等表达吲哚胺-2,3-双加氧酶，基于Transwell和阻断实验，这似乎是主要的免疫调节途径。SCD和非SCD MSC之间，参与造血干细胞（HSC）-MSC相互作用的关键基因表达变化极小。然而，IFN-γ刺激会改变其表达，特别是CXCL14、CXCL26、CX3CL1、CKITL和JAG1，这表明通过细胞因子刺激增强MSC表达的潜力。这些数据证明了从SCD患者中扩增BM源性MSC的可行性，根据国际细胞治疗协会的基本标准，这些MSC在表型和功能上与非SCD MSC没有差异，支持对自体MSC进行初步评估（主要是安全性评估），以增强单倍体HSC在SCD中的植入。
