Efficacy of Clinical-Grade Human Placental Mesenchymal Stromal Cells in Fetal Ovine Myelomeningocele Repair
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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 hours 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
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