Department of Human Oncology, 600 Highland Ave, University of Wisconsin, School of Medicine and Public Health, Madison, WI 53705 USA.
Department of Medicine, 600 Highland Ave, University of Wisconsin, School of Medicine and Public Health, Madison, WI 53705 USA.
Radiother Oncol. 2024 Mar;192:110093. doi: 10.1016/j.radonc.2024.110093. Epub 2024 Jan 13.
Salivary dysfunction is a significant side effect of radiation therapy for head and neck cancer (HNC). Preliminary data suggests that mesenchymal stromal cells (MSCs) can improve salivary function. Whether MSCs from HNC patients who have completed chemoradiation are functionally similar to those from healthy patients is unknown. We performed a pilot clinical study to determine whether bone marrow-derived MSCs [MSC(M)] from HNC patients could be used for the treatment of RT-induced salivary dysfunction.
An IRB-approved pilot clinical study was undertaken on HNC patients with xerostomia who had completed treatment two or more years prior. Patients underwent iliac crest bone marrow aspirate and MSC(M) were isolated and cultured. Culture-expanded MSC(M) were stimulated with IFNγ and cryopreserved prior to reanimation and profiling for functional markers by flow cytometry and ELISA. MSC(M) were additionally injected into mice with radiation-induced xerostomia and the changes in salivary gland histology and salivary production were examined.
A total of six subjects were enrolled. MSC(M) from all subjects were culture expanded to > 20 million cells in a median of 15.5 days (range 8-20 days). Flow cytometry confirmed that cultured cells from HNC patients were MSC(M). Functional flow cytometry demonstrated that these IFNγ-stimulated MSC(M) acquired an immunosuppressive phenotype. IFNγ-stimulated MSC(M) from HNC patients were found to express GDNF, WNT1, and R-spondin 1 as well as pro-angiogenesis and immunomodulatory cytokines. In mice, IFNγ-stimulated MSC(M) injection after radiation decreased the loss of acinar cells, decreased the formation of fibrosis, and increased salivary production.
MSC (M) from previously treated HNC patients can be expanded for auto-transplantation and are functionally active. Furthermore IFNγ-stimulated MSC(M) express proteins implicated in salivary gland regeneration. This study provides preliminary data supporting the feasibility of using autologous MSC(M) from HNC patients to treat RT-induced salivary dysfunction.
唾液功能障碍是头颈部癌症（HNC）放射治疗的一种显著副作用。初步数据表明间充质基质细胞（MSCs）可改善唾液功能。接受放化疗的 HNC 患者来源的 MSCs 是否在功能上与健康患者来源的 MSCs 相似尚不清楚。我们进行了一项初步的临床研究，以确定 HNC 患者的骨髓来源 MSCs [MSC（M）] 是否可用于治疗放疗引起的唾液功能障碍。
一项经机构审查委员会批准的初步临床研究针对治疗完成两年或两年以上的口干症 HNC 患者进行。患者接受髂嵴骨髓抽吸，分离和培养 MSC（M）。培养扩增的 MSC（M）在重新激活和通过流式细胞术和 ELISA 进行功能标志物分析之前用 IFNγ 刺激并冷冻保存。将 MSC（M）额外注入辐射诱导的口干症小鼠体内，检查唾液腺组织学和唾液产生的变化。
共纳入 6 名受试者。所有受试者的 MSC（M）均在中位数为 15.5 天（范围 8-20 天）的时间内培养扩增至超过 2000 万个细胞。流式细胞术证实，来自 HNC 患者的培养细胞为 MSC（M）。功能流式细胞术表明，这些 IFNγ 刺激的 MSC（M）获得了免疫抑制表型。从 HNC 患者中分离出的 IFNγ 刺激的 MSC（M）表达 GDNF、WNT1 和 R-spondin 1 以及促血管生成和免疫调节细胞因子。在小鼠中，辐射后注射 IFNγ 刺激的 MSC（M）可减少腺泡细胞的丢失，减少纤维化的形成，并增加唾液的产生。
先前接受治疗的 HNC 患者的 MSC（M）可扩增进行自体移植，且具有功能活性。此外，IFNγ 刺激的 MSC（M）表达参与唾液腺再生的蛋白质。这项研究提供了初步数据，支持使用来自 HNC 患者的自体 MSC（M）治疗放疗引起的唾液功能障碍的可行性。
