Placental mesenchymal stromal cells rescue ambulation in ovine myelomeningocele

Aijun Wang, Erin Brown, Lee Lankford, Benjamin A. Keller, Christopher D. Pivetti, Nicole A. Sitkin, Michael S. Beattie, Jacqueline C. Bresnahan, Diana L Farmer

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

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 with in 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.

Original languageEnglish (US)
Pages (from-to)659-669
Number of pages11
JournalStem cells translational medicine
Volume4
Issue number6
DOIs
StatePublished - 2015

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Keywords

  • Cellular therapy
  • Fetal stem cells
  • Mesenchymal stem cells
  • Placenta
  • Stem cell

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology

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