Early investigations into improving bowel and bladder function in fetal ovine myelomeningocele repair

Theodorou, Christina M.; Jackson, Jordan E.; Stokes, Sarah C.; Pivetti, Christopher D.; Kumar, Priyadarsini; Paxton, Zachary J.; Matsukuma, Karen; Yamashiro, Kaeli J.; Reynaga, Lizette; Hyllen, Alicia A.; Lorimier, Arthur J. de; Hassan, Maheen; Wang, Aijun; Farmer, Diana L.; Saadai, Payam

doi:10.1016/j.jpedsurg.2021.12.046

Cited by 6 publications

(3 citation statements)

References 44 publications

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“…Our findings for sphincter outcomes differ from those of Farmer et al, who found no differences in bladder function between lambs that underwent fetal MMC repair with cells and control lambs 26 . Our study is the first to show a potentially beneficial effect of UC‐MSCs on urinary function, as lambs that received this treatment showed no incontinence.…”

Section: Discussioncontrasting

confidence: 93%

Allogenic umbilical cord‐derived mesenchymal stromal cells improve motor function in prenatal surgical repair of myelomeningocele: An ovine model study

Athiel

Jouannic

Mauffré

et al. 2023

BJOG

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ObjectiveTo investigate the effects of an adjuvant allogenic umbilical cord mesenchymal stromal cell (UC‐MSC) patch applied during fetal surgery on motor and sphincter function in the ovine MMC model.DesignMMC defects were surgically created at 75 days of gestation and repaired 14 days later.PopulationOvine MMC model: fetal lambs.MethodsWe compared lambs that received a UC‐MSC patch with a control group of lambs that received an acellular patch.Main Outcome MeasuresClinical neurological assessment was performed at 2 and 24 hours of life and included determination of the Sheep Locomotor Rating scale (SLR), which has been validated in the ovine MMC model. Electrophysical examinations, spine scans and histological analyses were also performed.ResultsOf the 13 operated lambs, nine were born alive: five had of these had received a UC‐MSC patch and four an acellular patch. At 24 hours of life, lambs in the UC‐MSC group had a significantly higher score (14 versus 5, P = 0.04). Amyotrophy was significantly more common in the control group (75% versus 0%, P = 0.02). All the lambs in the control group and none of those in the UC‐MSC group were incontinent. No significant differences were observed between the UC‐MSC and control groups in terms of the presence of spontaneous EMG activity, nerve conduction or spinal evoked potentials. In the microscopic examination, lambs in the UC‐MSC group had less fibrosis between the spinal cord and the dermis (mean thickness, 453 versus 3921 μm, P = 0.03) and around the spinal cord (mean thickness, 47 versus 158 μm, P < 0.001). Examination of the spinal cord in the area of the MMC defect showed a higher large neuron density in the UC‐MSC group (14.5 versus 5.6 neurons/mm2, P < 0.001). No tumours were observed.ConclusionsFetal repair of MMC using UC‐MSC patches improves motor and sphincter function as well as spinal preservation and reduction of fibrosis.

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Section: Discussioncontrasting

confidence: 93%

Allogenic umbilical cord‐derived mesenchymal stromal cells improve motor function in prenatal surgical repair of myelomeningocele: An ovine model study

Athiel

Jouannic

Mauffré

et al. 2023

BJOG

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“…[ 25 ] The stem cell therapy alternative, mainly involving stem cells isolated from gestational tissues, have been reported to improve animal survival and guarantee in utero tissue repair in genetically and mechanically induced spina bifida. [ 11 , 26 – 28 ] Although promising, the inherent risks and hindrances of cell therapy are many and include but are not limited to issues with scalability, cell differentiation abilities and aging, bystander effect which reduces cell potency, number of cells reaching target sites, and therapeutic outcome. [ 29 ]…”

Section: Discussionmentioning

confidence: 99%

Amniotic fluid-derived stem cells: potential factories of natural and mimetic strategies for congenital malformations

Fon,

Steele,

Idowu

et al. 2024

Preprint

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Background Mesenchymal stem cells (MSCs) from gestational tissues represent promising strategies for in utero treatment of congenital malformations, but plasticity and required high-risk surgical procedures limit their use. Here we propose natural exosomes (EXOs) isolated from amniotic fluid-MSCs (AF-MSCs), and their mimetic counterparts (MIMs), as valid, stable, and minimally invasive therapeutic alternatives. Methods MIMs were generated from AF-MSCs by combining sequential filtration steps through filter membranes with different porosity and size exclusion chromatography columns. Physiochemical and molecular characterization was performed to compare them to EXOs released from the same number of cells. The possibility to exploit both formulations as mRNA-therapeutics was explored by evaluating cell uptake (using two different cell types, fibroblasts, and macrophages) and mRNA functionality overtime in an in vitro experimental setting as well as in an ex vivo, whole embryo culture using pregnant C57BL6 dams. Results Molecular and physiochemical characterization showed no differences between EXOs and MIMs, with MIMs determining a 3-fold greater yield. MIMs delivered a more intense and prolonged expression of mRNA encoding for green fluorescent protein (GFP) in macrophages and fibroblasts. An ex-vivo whole embryo culture demonstrated that MIMs mainly accumulate at the level of the yolk sac, while EXOs reach the embryo. Conclusions The present data confirms the potential application of EXOs for the prenatal repair of neural tube defects and proposes MIMs as prospective vehicles to prevent congenital malformations caused by in utero exposure to drugs.

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“…Additionally, long-term care of these animals to evaluate for this function is difficult given their comorbidities. While the use of anorectal manometry for bowel function evaluation and void volume for bladder function have been reported in the literature, there is currently no standardized evaluation for bowel or bladder function in any of the ovine models of MMC [39].…”

Section: Additional Scientific Rigor To the Modelmentioning

confidence: 99%

Evolution and Variations of the Ovine Model of Spina Bifida

Lee¹,

Du²,

Hassan³

et al. 2023

Fetal Diagn Ther

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Spina bifida is the most common congenital anomaly of the central nervous system and the first non-fatal fetal lesions to be addressed by fetal intervention. While research in spina bifida has been performed in rodent, non-human primate and canine models, sheep have been a model organism for the disease. This review summarizes the history of development of the ovine model of spina bifida, previous applications, and translation into clinical studies. Initially used by Meuli et al., fetal myelomeningocele defect creation and in utero repair demonstrated motor function preservation. The addition of myelotomy in this model can reproduce hindbrain herniation malformations, which is the leading cause of mortality and morbidity in humans. Since inception, the ovine models have been validated numerous times as the ideal large animal model for fetal repair, with both locomotive scoring and spina bifida defect scoring adding to the rigor of this model. The ovine model has been used to study different methods of myelomeningocele defect repair, the application of various tissue engineering techniques for neuroprotection and bowel and bladder function. The results of these large animal studies have been translated into human clinical trials including MOMS (Management of Meningocele Study) trial that established current standard of care for prenatal repair of spina bifida defects, and the ongoing trials including the CuRe (Cellular Therapy for In Utero Repair of Myelomeningocele) trial using a stem cell patch for repair. The advancement of these live saving and life altering therapy began in sheep models, and this notable model continues to be used to further the field including current work with stem cell therapy.

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Early investigations into improving bowel and bladder function in fetal ovine myelomeningocele repair

Cited by 6 publications

References 44 publications

Allogenic umbilical cord‐derived mesenchymal stromal cells improve motor function in prenatal surgical repair of myelomeningocele: An ovine model study

Allogenic umbilical cord‐derived mesenchymal stromal cells improve motor function in prenatal surgical repair of myelomeningocele: An ovine model study

Amniotic fluid-derived stem cells: potential factories of natural and mimetic strategies for congenital malformations

Evolution and Variations of the Ovine Model of Spina Bifida

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