Human induced pluripotent stem cell-derived neural crest stem cells integrate into the injured spinal cord in the fetal lamb model of myelomeningocele

Payam Saadai, Aijun Wang, Yvette S. Nout, Timothy L. Downing, Katrine Lofberg, Michael S. Beattie, Jacqueline C. Bresnahan, Song Li, Diana L Farmer

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Background/Purpose: Neurological function in patients with myelomeningocele (MMC) is limited even after prenatal repair. Neural crest stem cells (NCSCs) can improve neurological function in models of spinal cord injury. We aimed to evaluate the survival, integration, and differentiation of human NCSCs derived from induced pluripotent stem cells (iPSC-NCSCs) in the fetal lamb model of MMC. Methods: Human iPSCs derived from skin fibroblasts were differentiated into NCSCs in vitro, mixed with hydrogel, and seeded on nanofibrous scaffolds for surgical transplantation. Fetal lambs (n=2) underwent surgical MMC creation and repair with iPSC-NCSC seeded scaffolds. Gross necropsy and immunohistochemistry were performed at term. Results: IPSC-NCSCs expressed NCSC markers, maintained > 95% viability, and demonstrated neuronal differentiation in vitro. Immunohistochemical analysis of repaired spinal cords thirty days after transplantation demonstrated the co-localization of human nuclear mitotic apparatus protein (NuMA) and Neurofilament M subunit (NFM) in the area of spinal cord injury. No gross tumors were identified. Conclusions: Human iPSC-NCSCs survived, integrated, and differentiated into neuronal lineage in the fetal lamb model of MMC. This is the first description of human stem cell engraftment in a model of fetal MMC and supports the concept of using NCSCs to address spinal cord damage in MMC.

Original languageEnglish (US)
Pages (from-to)158-163
Number of pages6
JournalJournal of Pediatric Surgery
Volume48
Issue number1
DOIs
StatePublished - Jan 2013

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Induced Pluripotent Stem Cells
Meningomyelocele
Neural Stem Cells
Neural Crest
Spinal Cord
Spinal Cord Injuries
Transplantation
Intermediate Filaments
Hydrogel
Stem Cells
Fibroblasts
Immunohistochemistry
Skin
Survival

Keywords

  • Fetal surgery
  • Myelomeningocele
  • Spina bifida
  • Spinal cord injury
  • Stem cells

ASJC Scopus subject areas

  • Surgery
  • Pediatrics, Perinatology, and Child Health

Cite this

Human induced pluripotent stem cell-derived neural crest stem cells integrate into the injured spinal cord in the fetal lamb model of myelomeningocele. / Saadai, Payam; Wang, Aijun; Nout, Yvette S.; Downing, Timothy L.; Lofberg, Katrine; Beattie, Michael S.; Bresnahan, Jacqueline C.; Li, Song; Farmer, Diana L.

In: Journal of Pediatric Surgery, Vol. 48, No. 1, 01.2013, p. 158-163.

Research output: Contribution to journalArticle

Saadai, Payam ; Wang, Aijun ; Nout, Yvette S. ; Downing, Timothy L. ; Lofberg, Katrine ; Beattie, Michael S. ; Bresnahan, Jacqueline C. ; Li, Song ; Farmer, Diana L. / Human induced pluripotent stem cell-derived neural crest stem cells integrate into the injured spinal cord in the fetal lamb model of myelomeningocele. In: Journal of Pediatric Surgery. 2013 ; Vol. 48, No. 1. pp. 158-163.
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abstract = "Background/Purpose: Neurological function in patients with myelomeningocele (MMC) is limited even after prenatal repair. Neural crest stem cells (NCSCs) can improve neurological function in models of spinal cord injury. We aimed to evaluate the survival, integration, and differentiation of human NCSCs derived from induced pluripotent stem cells (iPSC-NCSCs) in the fetal lamb model of MMC. Methods: Human iPSCs derived from skin fibroblasts were differentiated into NCSCs in vitro, mixed with hydrogel, and seeded on nanofibrous scaffolds for surgical transplantation. Fetal lambs (n=2) underwent surgical MMC creation and repair with iPSC-NCSC seeded scaffolds. Gross necropsy and immunohistochemistry were performed at term. Results: IPSC-NCSCs expressed NCSC markers, maintained > 95{\%} viability, and demonstrated neuronal differentiation in vitro. Immunohistochemical analysis of repaired spinal cords thirty days after transplantation demonstrated the co-localization of human nuclear mitotic apparatus protein (NuMA) and Neurofilament M subunit (NFM) in the area of spinal cord injury. No gross tumors were identified. Conclusions: Human iPSC-NCSCs survived, integrated, and differentiated into neuronal lineage in the fetal lamb model of MMC. This is the first description of human stem cell engraftment in a model of fetal MMC and supports the concept of using NCSCs to address spinal cord damage in MMC.",
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AB - Background/Purpose: Neurological function in patients with myelomeningocele (MMC) is limited even after prenatal repair. Neural crest stem cells (NCSCs) can improve neurological function in models of spinal cord injury. We aimed to evaluate the survival, integration, and differentiation of human NCSCs derived from induced pluripotent stem cells (iPSC-NCSCs) in the fetal lamb model of MMC. Methods: Human iPSCs derived from skin fibroblasts were differentiated into NCSCs in vitro, mixed with hydrogel, and seeded on nanofibrous scaffolds for surgical transplantation. Fetal lambs (n=2) underwent surgical MMC creation and repair with iPSC-NCSC seeded scaffolds. Gross necropsy and immunohistochemistry were performed at term. Results: IPSC-NCSCs expressed NCSC markers, maintained > 95% viability, and demonstrated neuronal differentiation in vitro. Immunohistochemical analysis of repaired spinal cords thirty days after transplantation demonstrated the co-localization of human nuclear mitotic apparatus protein (NuMA) and Neurofilament M subunit (NFM) in the area of spinal cord injury. No gross tumors were identified. Conclusions: Human iPSC-NCSCs survived, integrated, and differentiated into neuronal lineage in the fetal lamb model of MMC. This is the first description of human stem cell engraftment in a model of fetal MMC and supports the concept of using NCSCs to address spinal cord damage in MMC.

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