Scanning electron microscopy of fetal murine myelomeningocele reveals growth and development of the spinal cord in early gestation and neural tissue destruction around birth

Dorothea Stiefel  1 , Martin Meuli

Previous studies demonstrated that the spinal cord within a fetal myelomeningocele (MMC) lesion suffers progressive destruction during gestation. This study aims at elucidating this pathophysiologic feature on a cellular and ultrastructural level in a model of genetically determined MMC.

Journal: Journal of Pediatric Surgery (Volume 42, Issue 9, September 2007, Pages 1561-1565)

Date: 01/09/2007

1 Neural Development Unit, Institute of Child Health, University College London, London, WC1N 1EH United Kingdom.

Fetal spina bifida in a mouse model: loss of neural function in utero

Dorothea Stiefel  1 , Andrew J Copp, Martin Meuli

The devastating neurological deficit associated with myelomeningocele has previously been assumed to be a direct and inevitable consequence of the primary malformation-failure of neural tube closure. An alternative view is that secondary damage to the pathologically exposed spinal cord tissue in utero is responsible for the neurological deficiency. If the latter mechanism were shown to be correct, it would provide an objective rationale for the performance of in utero surgery for myelomeningocele, because coverage of the exposed spinal cord could be expected to alleviate or perhaps prevent neurodegeneration. To examine this question, the authors studied the development of neuronal connections and neurological function of mice during fetal and neonatal stages in a genetic model of exposed lumbosacral spina bifida.

Journal: JNS Journal of Neurosurgery (Volume 106: Issue 3, March 2007)

Date: 01/03/2007

1 Department of Pediatric Surgery, University Children's Hospital Zurich, Switzerland.

Tethering of the spinal cord in mouse fetuses and neonates with spina bifida

Dorothea Stiefel  1 , Takashi Shibata, Martin Meuli, Patrick G Duffy, Andrew J Copp

Tethering of the spinal cord is a well-known complication in humans with spina bifida aperta or occulta. Its pathogenesis consists of a pathological fixation of the spinal cord resulting in traction on the neural tissue which, in turn, leads to ischemia and progressive neurological deterioration. Although well established in humans, this phenomenon has not been described in animal models of spina bifida.

Journal: JNS Journal of Neurosurgery: Spine (Volume 99: Issue 2, Sep. 2003)

Date: 01/09/2003

1 Neural Development Unit, Institute of Child Health, University College London, United Kingdom.

Physiologically low oxygen concentrations in fetal skin regulate hypoxia-inducible factor 1 and transforming growth factor-beta3.

Annette Scheid1, Roland H Wenger1,Leonhard Schäffer1,Isabelle Camenisch1,Oliver Distler1, Andrej Ferenc1, Heidi Cristina1, Heather E Ryan1, Randall S Johnson1, Klaus F Wagner1, Urs G Stauffer1, Christian Bauer1, Max Gassmann1, Martin Meuli1

In the first-trimester mammalian fetus, skin wounds heal with perfect reconstitution of the dermal architecture without scar formation. Understanding environmental molecular regulation in fetal wound healing may reveal scar-limiting therapeutical strategies for the prevention of postnatal scarring wound repair. Therefore, we performed studies on fetal skin oxygenation and skin and wound expression of hypoxia-inducible factor 1alpha (HIF-1alpha) in the sheep model in vivo and performed studies on the potential relevance of HIF-1alpha during wound healing in vitro. Skin oxygen partial pressure levels were hypoxic throughout normal development. In nonscarring fetal skin at gestation day (GD)60, HIF-1alpha could be detected neither in healthy nor in wounded tissue. At GD100, in wounds with minimal scar formation, HIF-1alpha was expressed in fibroblasts and was markedly up-regulated at the wound edge. In scarring fetal wounds at GD120, HIF-1alpha was predominantly expressed in inflammatory cells. Expression of transforming growth factor beta3 (TGF-beta3), a potent antiscarring cytokine, overlapped with HIF-1a expression at GD100. HIF-1alpha-deficient mouse embryonic fibroblasts showed impaired migratory capabilities and demonstrated that TGF-beta3, but not proscarring TGF-beta1, manifests hypoxia- and HIF-1alpha-dependent regulation. In conclusion, HIF-1alpha-dependent regulation of a potent antiscarring cytokine may provide new strategies for antiscarring manipulation of wound healing.

Journal: PubMed

Date: 20/02/2003

Department of Surgery, University Children's Hospital of Zürich, Switzerland.

Fetal Surgery for Myelomeningocele: Panacea or Peril?

Shinjiro Hirose  1 , Claudia Meuli-Simmen, Martin Meuli

Myelomeningocele affects thousands of children worldwide with devastating consequences. In an effort to improve neurologic outcome, fetal surgery has been performed for myelomeningocele for the past 5 years. Sensorimotor function is not appreciably improved, although there may be a reduction in hindbrain herniation and a decreased need for ventriculoperitoneal shunting. The long-term clinical consequences of these findings are not clear. What is clear, however, is that further study in the form of a prospective, randomized trial is mandatory.

Journal: World Journal of Surgery - published online: December 19, 2002

Date: 06/01/2003

1 The Fetal Treatment Center, Department of Surgery, Division of Pediatric Surgery, University of California, San Francisco, 513 Parnassus Avenue, Room HSW 1601, San Francisco, California 94143-0570, USA.