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3D skin fixes backbone birth defect in rat pups

Myelomeningocele is a severe congenital defect in which the backbone and spinal canal do not close before birth, putting affected babies at risk for lifelong neurologic problems. In a preclinical study, researchers developed a stem cell-based therapy for generating skin grafts to cover myelomeningocele defects before birth. They first generated artificial skin from human induced pluripotent stem cells (iPSCs), and then successfully transplanted the skin grafts into rat fetuses with myelomeningocele.


Myelomeningocele is the most serious and common form of spina bifida, a neural tube defect in which bones of the spine do not completely form. As a result, parts of the spinal cord and nerves are partially open on the spine. A baby born with this disorder typically has an open area (or a fluid-filled sac) on the mid to lower back. Most children with this condition are at risk of brain damage as fluid builds up in their brains from circulation problems. They also often experience symptoms such as loss of bladder or bowel control, loss of feeling in the legs or feet, and paralysis of the legs from the affected nerve damage to their spine.
"We provide preclinical proof of concept for a fetal therapy that could improve outcomes and prevent lifelong complications associated with myelomeningocele one of the most severe birth defects. Since our fetal cell treatment is minimally invasive, it has the potential to become a much-needed novel treatment for myelomeningocele."

Akihiro Umezawa PhD, Japan's National Research Institute for Child Health and Development, and senior author.

The work was published June 6th in Stem Cell Reports.

Babies born with myelomeningocele usually undergo surgery to repair the defect within the first few days of life. Some highly specialized centers also offer intrauterine surgery to close the defect before the baby is born. Although prenatal surgery can improve later neurological outcomes compared with post-natal surgery, it is also associated with higher rates of preterm birth and other serious complications, underscoring the need for safe and effective fetal therapies in-utero.

To address this problem, Umezawa and his team set out to develop a minimally invasive approach for generating and transplanting skin grafts that could cover large myelomeningocele defects earlier during pregnancy, potentially improving long-term outcomes while reducing surgical risks. In particular, they were interested in using iPSC technology, which involves genetically reprogramming patients' cells to an embryonic stem cell-like state and then converting these immature cells into specialized cell types found in different parts of the body. This approach avoids ethical concerns while offering the advantages of a potentially unlimited source of various cell types for transplantation, as well as minimal risk of graft rejection by the immune system.

In the study, researchers first generated human iPSCs from fetal cells taken from the amniotic fluid of two pregnancies with severe fetal disease (Down syndrome and twin-twin3 transfusion syndrome or TTTS). TTTS is a condition in which the blood passes unequally between twins that share a placenta. The smaller twin (donor) pumps blood to the larger twin (recipient). Without intervention, the condition can be fatal for both twins.

The team used a chemical cocktail in a novel protocol to turn the iPSCs into skin cells and treated these skin cells with more compounds such as epidermal growth factor to promote their growth into multi-layered skin. In total, it took approximately 14 weeks from amniotic fluid preparation to 3D skin generation, which allows for transplantation to be performed in humans during the therapeutic window of 28-29 weeks gestation.

Next, researchers transplanted the 3D skin grafts into 20 rat fetuses through a small incision in their mother's uterine wall. The grafts grew to partially cover the myelomeningocele defects in eight of the newborn rats and completely covered the defects in four of the newborn rats, protecting the spinal cord from direct exposure in the external environment. Moreover, the engrafted 3D skin regenerated along with the growth of the fetus and accelerated skin coverage throughout the pregnancy. Also, the transplanted skin cells did not lead to tumor formation, but did significantly decrease birth weight and body length.
"We are encouraged by our results and believe that our fetal stem cell therapy has great potential to become a novel treatment for myelomeningocele."

Akihiro Umezawa PhD

Summary
Myelomeningocele (MMC) is a congenital disease without genetic abnormalities. Neurological symptoms are irreversibly impaired after birth, and no effective treatment has been reported to date. Only surgical repairs have been reported so far. In this study, we performed antenatal treatment of MMC with an artificial skin using induced pluripotent stem cells (iPSCs) generated from a patient with Down syndrome (AF-T21-iPSCs) and twin-twin transfusion syndrome (AF-TTTS-iPSCs) to a rat model. We manufactured three-dimensional skin with epidermis generated from keratinocytes derived from AF-T21-iPSCs and AF-TTTS-iPSCs and dermis of human fibroblasts and collagen type I. For generation of epidermis, we developed a protocol using Y-27632 and epidermal growth factor. The artificial skin was successfully covered over MMC defect sites during pregnancy, implying a possible antenatal surgical treatment with iPSC technology.

Keywords: induced pluripotent stem cells, myelomeningocele, fetal therapy, keratinocytes, rock inhibitor, epidermal growth factor, amniotic fluid, polyhydramnion This study was supported by a grant from JSPS KAKENHI.

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Jun 12, 2017   Fetal Timeline   Maternal Timeline   News   News Archive




A photo of "iSkin" (three-dimensional cultured skin) made from human iPSCs.
Image Credit: Kazuhiro Kajiwara.



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