Development of a Locomotor Rating Scale for Testing Motor Function in Sheep

Brown, Erin G.; Keller, B; Pivetti, Christopher D.; Sitkin, Nicole; Wang, Aijun; Farmer, Diana L.; Bresnahan, Jacqueline C.

doi:10.1016/j.jpedsurg.2015.01.002

Cited by 28 publications

(30 citation statements)

References 13 publications

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“…All experimental lambs surviving to term ( n = 12) were analyzed. The average GA at birth was 145.7 days (range, 138–152), and within 24 hours of birth, motor function was assessed using the SLR scale [19]. Three untreated newborn lambs (no MMC defect) exhibited normal motor function (SLR score of 15) and served as positive controls.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Placental Mesenchymal Stromal Cells Rescue Ambulation in Ovine Myelomeningocele

Wang

Brown

Lankford

et al. 2015

Stem Cells Translational Medicine

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110

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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. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:659-669 SIGNIFICANCEThis 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.

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Section: Resultsmentioning

confidence: 99%

“…The lambs were delivered at term (GA approximately 145 days). After birth, motor function was evaluated for all lambs, in addition to 3 normal, negative controls, using the sheep locomotor rating (SLR) scale, as previously described [19]. In brief, motor function in 7 categories was observed and scored on a scale of 0–15.…”

Section: Methodsmentioning

confidence: 99%

Placental Mesenchymal Stromal Cells Rescue Ambulation in Ovine Myelomeningocele

Wang

Brown

Lankford

et al. 2015

Stem Cells Translational Medicine

Self Cite

110

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“…145 days' GA) via spontaneous vaginal delivery. Motor function was evaluated for all lambs with the Sheep Locomotor Rating (SLR) scale as previously described [17]. The scale assesses motor function in seven categories and results in a score from 1 to 15, with normal function scoring 15 and complete hind limb paralysis scoring 0.…”

Section: Methodsmentioning

confidence: 99%

Age Does Matter: A Pilot Comparison of Placenta-Derived Stromal Cells for in utero Repair of Myelomeningocele Using a Lamb Model

Brown¹,

Keller²,

Lankford³

et al. 2015

Fetal Diagn Ther

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Introduction: Fetal amniotic membranes (FM) have been shown to preserve spinal cord histology in the fetal sheep model of myelomeningocele (MMC). This study compares the effectiveness of placenta-derived mesenchymal stromal cells (PMSCs) from early-gestation versus term-gestation placenta to augment FM repair to improve distal motor function in a sheep model. Methods: Fetal lambs (n = 4) underwent surgical MMC creation followed by repair with FM patch with term-gestation PMSCs (n = 1), FM with early-gestation PMSCs (n = 1), FM only (n = 1), and skin closure only (n = 1). Histopathology and motor assessment was performed. Results: Histopathologic analysis demonstrated increased preservation of spinal cord architecture and large neurons in the lamb repaired with early-gestation cells compared to all others. Lambs repaired with skin closure only, FM alone, and term-gestation PMSCs exhibited extremely limited distal motor function; the lamb repaired with early-gestation PMSCs was capable of normal ambulation. Discussion: This pilot study is the first in vivo comparison of different gestational-age placenta-derived stromal cells for repair in the fetal sheep MMC model. The preservation of large neurons and markedly improved motor function in the lamb repaired with early-gestation cells suggest that early-gestation placental stromal cells may exhibit unique properties that augment in utero MMC repair to improve paralysis.

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“…We note that the BBB (Basso, Beattie and Bresnahan) rating scale, 26 used routinely for assessing post-SCI hindlimb locomotor function in small animal (rodent) models, has recently been adapted for use in lambs. 27 However, our work was begun before the revised BBB scale was available and, at that time, the TIBS rating scale had already been validated for large animal models. Hence, we adopted the latter for assessment in these preliminary studies with our experimental sheep but will consider use of the former in future studies, as it is ovine-specific.…”

Section: Anesthesia Surgical and Injury-evaluation Protocolsmentioning

confidence: 99%