Cabanillas Stanchi Karin Melanie, Böhringer Judith, Strölin Manuel, Groeschel Samuel, Lenglinger Katrin, Treuner Claudia, Kehrer Christiane, Laugwitz Lucia, Bevot Andrea, Kaiser Nadja, Schumm Michael, Lang Peter, Handgretinger Rupert, Krägeloh-Mann Ingeborg, Müller Ingo, Döring Michaela
General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany.
Neuropediatrics, University Children's Hospital Tübingen, Tübingen, Germany.
Stem Cells Dev. 2022 Apr;31(7-8):163-175. doi: 10.1089/scd.2021.0352.
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder primarily affecting the white matter of the nervous system that results from a deficiency of the arylsulfatase A (ARSA). Mesenchymal stem cells (MSCs) are able to secrete ARSA and have shown beneficial effects in MLD patients. In this retrospective analysis, 10 pediatric MLD patients [mesenchymal stem cell group (MSCG)] underwent allogeneic hematopoietic stem cell transplantation (HSCT) and received two applications of 2 × 10 MSCs/kg bodyweight at day +30 and +60 after HSCT between 2007 and 2018. MSC safety, occurrence of graft-versus-host disease (GvHD), blood ARSA levels, chimerism, cell regeneration and engraftment, magnetic resonance imaging (MRI) changes, and the gross motor function were assessed within the first year of HSCT. The long-term data included clinical outcomes and safety aspects of MSCs. Data were compared to a control cohort of seven pediatric MLD patients [control group (CG)] who underwent HSCT only. The application of MSC in pediatric MLD patients after allogeneic HSCT was safe and well tolerated, and long-term potentially MSC-related adverse effects up to 13.5 years after HSCT were not observed. Patients achieved significantly higher ARSA levels (CG: median 1.03 nmol·10 and range 0.41-1.73 | MSCG: median 1.58 nmol·10 and range 0.44-2.6; < 0.05), as well as significantly higher leukocyte ( < 0.05) and thrombocyte ( < 0.001) levels within 365 days of MSC application compared to CG patients. Statistically significant effects on acute GvHD, regeneration of immune cells, MRI changes, gross motor function, and clinical outcomes were not detected. In conclusion, the application of MSCs in pediatric MLD patients after allogeneic HSCT was safe and well tolerated. The two applications of 2 × 10/kg allogeneic MSCs were followed by improved engraftment and hematopoiesis within the first year after HSCT. Larger, prospective trials are necessary to evaluate the impact of MSC application on engraftment and hematopoietic recovery.
异染性脑白质营养不良（MLD）是一种溶酶体贮积症，主要影响神经系统的白质，由芳基硫酸酯酶A（ARSA）缺乏引起。间充质干细胞（MSC）能够分泌ARSA，并已在MLD患者中显示出有益效果。在这项回顾性分析中，10例儿科MLD患者[间充质干细胞组（MSCG）]接受了异基因造血干细胞移植（HSCT），并在2007年至2018年间于HSCT后第30天和第60天接受了两次2×10个MSC/kg体重的输注。在HSCT的第一年内评估了MSC的安全性、移植物抗宿主病（GvHD）的发生情况、血液ARSA水平、嵌合现象、细胞再生和植入情况、磁共振成像（MRI）变化以及粗大运动功能。长期数据包括MSC的临床结果和安全性方面。将数据与仅接受HSCT的7例儿科MLD患者的对照组[对照组（CG）]进行比较。异基因HSCT后在儿科MLD患者中应用MSC是安全的且耐受性良好，并且未观察到HSCT后长达13.5年的与MSC潜在相关的长期不良反应。与CG组患者相比，患者在应用MSC后365天内ARSA水平显著更高（CG组：中位数1.03 nmol·10，范围0.41 - 1.73 | MSCG组：中位数1.58 nmol·10，范围0.44 - 2.6；P < 0.05），白细胞水平（P < 0.05）和血小板水平（P < 0.001）也显著更高。未检测到对急性GvHD、免疫细胞再生、MRI变化、粗大运动功能和临床结果有统计学意义的影响。总之，异基因HSCT后在儿科MLD患者中应用MSC是安全的且耐受性良好。在HSCT后的第一年内，两次2×10/kg异基因MSC的输注后植入和造血情况得到改善。需要进行更大规模的前瞻性试验来评估MSC应用对植入和造血恢复的影响。
