Efficacy of clinical-grade human placental mesenchymal stromal cells in fetal ovine myelomeningocele repair

Christina M. Theodorou, Sarah C. Stokes, Jordan E. Jackson, Christopher D. Pivetti, Priyadarsini Kumar, Kaeli J. Yamashiro, Zachary J. Paxton, Lizette Reynaga, Alicia A. Hyllen, Aijun Wang, Diana L. Farmer

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: While fetal repair of myelomeningocele (MMC) revolutionized management, many children are still unable to walk independently. Preclinical studies demonstrated that research-grade placental mesenchymal stromal cells (PMSCs) prevent paralysis in fetal ovine MMC, however this had not been replicated with clinical-grade cells that could be used in an upcoming human clinical trial. We tested clinical-grade PMSCs seeded on an extracellular matrix (PMSC-ECM) in the gold standard fetal ovine model of MMC. Methods: Thirty-five ovine fetuses underwent MMC defect creation at a median of 76 days gestational age, and defect repair at 101 days gestational age with application of clinical-grade PMSC-ECM (3 × 105 cells/cm2, n = 12 fetuses), research-grade PMSC-ECM (3 × 105 cells/cm2, three cell lines with n = 6 (Group 1), n = 6 (Group 2), and n = 3 (Group 3) fetuses, respectively) or ECM without PMSCs (n = 8 fetuses). Three normal lambs underwent no surgical interventions. The primary outcome was motor function measured by the Sheep Locomotor Rating scale (SLR, range 0: complete paralysis to 15: normal ambulation) at 24 h of life. Correlation of lumbar spine large neuron density with SLR was evaluated. Results: Clinical-grade PMSC-ECM lambs had significantly better motor function than ECM-only lambs (SLR 14.5 vs. 6.5, p = 0.04) and were similar to normal lambs (14.5 vs. 15, p = 0.2) and research-grade PMSC-ECM lambs (Group 1: 14.5 vs. 15, p = 0.63; Group 2: 14.5 vs. 14.5, p = 0.86; Group 3: 14.5 vs. 15, p = 0.50). Lumbar spine large neuron density was strongly correlated with motor function (r = 0.753, p<0.001). Conclusions: Clinical-grade placental mesenchymal stromal cells seeded on an extracellular matrix rescued ambulation in a fetal ovine myelomeningocele model. Lumbar spine large neuron density correlated with motor function, suggesting a neuroprotective effect of the PMSC-ECM in prevention of paralysis. A first-in-human clinical trial of PMSCs in human fetal myelomeningocele repair is underway.

Original languageEnglish (US)
JournalJournal of pediatric surgery
DOIs
StateAccepted/In press - 2021

Keywords

  • Cellular therapy
  • Fetal surgery
  • Myelomeningocele
  • Spina bifida

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Surgery

Fingerprint

Dive into the research topics of 'Efficacy of clinical-grade human placental mesenchymal stromal cells in fetal ovine myelomeningocele repair'. Together they form a unique fingerprint.

Cite this