Wang Aijun, Brown Erin G, Lankford Lee, Keller Benjamin A, Pivetti Christopher D, Sitkin Nicole A, Beattie Michael S, Bresnahan Jacqueline C, Farmer Diana L
Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis, Health System, Sacramento, California, USA; Brain and Spinal Injury Center, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA
Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis, Health System, Sacramento, California, USA; Brain and Spinal Injury Center, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
Stem Cells Transl Med. 2015 Jun;4(6):659-69. doi: 10.5966/sctm.2014-0296. Epub 2015 Apr 24.
Myelomeningocele (MMC)-commonly known as spina bifida-is a congenital birth defect that causes lifelong paralysis, incontinence, musculoskeletal deformities, and severe cognitive disabilities. The recent landmark Management of Myelomeningocele Study (MOMS) demonstrated for the first time in humans that in utero surgical repair of the MMC defect improves lower limb motor function, suggesting a capacity for improved neurologic outcomes in this disorder. However, functional recovery was incomplete, and 58% of the treated children were unable to walk independently at 30 months of age. In the present study, we demonstrate that using early gestation human placenta-derived mesenchymal stromal cells (PMSCs) to augment in utero repair of MMC results in significant and consistent improvement in neurologic function at birth in the rigorous fetal ovine model of MMC. In vitro, human PMSCs express characteristic MSC markers and trilineage differentiation potential. Protein array assays and enzyme-linked immunosorbent assay show that PMSCs secrete a variety of immunomodulatory and angiogenic cytokines. Compared with adult bone marrow MSCs, PMSCs secrete significantly higher levels of brain-derived neurotrophic factor and hepatocyte growth factor, both of which have known neuroprotective capabilities. In vivo, functional and histopathologic analysis demonstrated that human PMSCs mediate a significant, clinically relevant improvement in motor function in MMC lambs and increase the preservation of large neurons within the spinal cord. These preclinical results in the well-established fetal ovine model of MMC provide promising early support for translating in utero stem cell therapy for MMC into clinical application for patients.
This study presents placenta-derived mesenchymal stromal cell (PMSC) treatment as a potential therapy for myelomeningocele (MMC). Application of PMSCs can augment current in utero surgical repair in the well-established and rigorously applied fetal lamb model of MMC. Treatment with human PMSCs significantly and dramatically improved neurologic function and preserved spinal cord neuron density in experimental animals. Sixty-seven percent of the PMSC-treated lambs were able to ambulate independently, with two exhibiting no motor deficits whatsoever. In contrast, none of the lambs treated with the vehicle alone were capable of ambulation. The locomotor rescue demonstrated in PMSC-treated lambs indicates great promise for future clinical trials to improve paralysis in children afflicted with MMC.
脊髓脊膜膨出（MMC）——通常称为脊柱裂——是一种先天性出生缺陷，会导致终身瘫痪、大小便失禁、肌肉骨骼畸形和严重的认知障碍。最近具有里程碑意义的脊髓脊膜膨出管理研究（MOMS）首次在人类中证明，子宫内手术修复MMC缺陷可改善下肢运动功能，这表明该疾病在神经学预后方面有改善的潜力。然而，功能恢复并不完全，58%接受治疗的儿童在30个月大时仍无法独立行走。在本研究中，我们证明，在严格的胎儿绵羊MMC模型中，使用早期妊娠人胎盘来源的间充质基质细胞（PMSC）增强子宫内MMC修复可在出生时显著且持续地改善神经功能。在体外，人PMSC表达特征性的MSC标志物和三系分化潜能。蛋白质阵列分析和酶联免疫吸附测定表明，PMSC分泌多种免疫调节和血管生成细胞因子。与成人骨髓间充质干细胞相比，PMSC分泌的脑源性神经营养因子和肝细胞生长因子水平显著更高，这两种因子都具有已知的神经保护能力。在体内，功能和组织病理学分析表明，人PMSC介导MMC羔羊运动功能的显著、临床相关改善，并增加脊髓内大神经元的保留。在成熟的胎儿绵羊MMC模型中的这些临床前结果为将子宫内干细胞治疗MMC转化为患者的临床应用提供了有希望的早期支持。
本研究提出胎盘来源的间充质基质细胞（PMSC）治疗作为脊髓脊膜膨出（MMC）的一种潜在疗法。在成熟且严格应用的胎儿绵羊MMC模型中，PMSC 的应用可增强当前的子宫内手术修复。用人PMSC治疗可显著且极大地改善实验动物的神经功能并保留脊髓神经元密度。67%接受PMSC治疗的羔羊能够独立行走，其中两只没有任何运动缺陷。相比之下，仅接受载体治疗的羔羊均无法行走。PMSC治疗的羔羊中表现出的运动功能挽救为未来改善患有MMC儿童瘫痪的临床试验带来了巨大希望。
