Mechanism of SHED-derived HGF in treating chronic perinatal brain injury
Illustration Credit: Yoshiaki Sato
Scientific Frontline: "At a Glance" Summary: Stem Cells for Treating Cerebral Palsy
- Main Discovery: Researchers demonstrated that stem cells derived from human exfoliated deciduous teeth effectively treat cerebral palsy in animal models, even when administered during the chronic phase after motor deficits have already emerged.
- Methodology: The research team induced unilateral hypoxic-ischemic brain injury in seven-day-old rats to mimic hemiplegic cerebral palsy and administered the stem cells intravenously at five, seven, and nine weeks of age. They subsequently evaluated the subjects using horizontal ladder, cylinder, and shuttle avoidance tests to assess both motor and cognitive functions.
- Key Data: Rats treated with the stem cells exhibited a significantly lower number of slips on the horizontal ladder test at four months, relied more on their impaired forelimbs, and demonstrated superior learning and memory in shuttle avoidance tests compared to the untreated control group.
- Significance: This marks the first animal study to prove that stem cell therapy can restore neurological function and promote new nervous tissue growth via hepatocyte growth factor in the later stages of cerebral palsy, successfully circumventing the ethical concerns associated with other stem cell sources.
- Future Application: Clinical studies are currently evaluating the safety and tolerability of intravenous autologous stem cell doses in children with cerebral palsy, with plans for large-scale trials to establish this approach as a standard clinical treatment option.
- Branch of Science: Regenerative Medicine, Pediatrics, and Neurology.
Researchers in Japan demonstrated, for the first time in animal models, that stem cell treatment can be effective even when initiated after motor deficits appear in cerebral palsy.
Cerebral palsy is a condition usually caused by brain damage before or during birth, resulting in impaired posture and movement. Early symptoms are typically subtle, which may delay diagnosis until more obvious signs appear as the child grows.
Recent animal studies show that stem cell therapy may help restore neurological function when initiated in the acute or subacute phase, typically within a few weeks after birth. While some clinical research suggests possible benefits even in later stages, confirmatory clinical trials have not yet been published.
Now, a Japanese research team has demonstrated in rat experiments that stem cells from human primary tooth pulp may help treat chronic-phase cerebral palsy.
“This is the first animal study to show that stem cell treatment works even after motor deficits have already appeared,” said Clinical Professor Yoshiaki Sato of Nagoya University Hospital, the study’s corresponding author. The findings were published in the journal Stem Cell Research & Therapy.
Cerebral palsy affects two to three of every 1,000 live births, and there is currently no cure. The primary cause is hypoxic-ischemic encephalopathy (HIE), which results from reduced oxygen and blood flow to the brain.
“Our team is collaborating with S-Quatre, a Japanese biotechnology company, to develop a new therapeutic approach for HIE using stem cells from human exfoliated deciduous teeth (SHED),” Sato said. “These stem cells are collected from baby teeth that have naturally fallen out and would otherwise be discarded. This method avoids the ethical concerns associated with other stem cell sources.”
A research team led by Sato, Dr. Takahiro Kanzawa, and Professor Yoshiyuki Takahashi at Nagoya University Graduate School of Medicine and Nagoya University Hospital, in collaboration with S-Quatre, conducted an experimental study to determine whether SHED-based treatment remains effective in the chronic phase of cerebral palsy.
Animal model experiments
The researchers created cerebral palsy models by inducing unilateral hypoxic-ischemic brain injury in 7-day-old rats, resulting in one-sided motor impairment like hemiplegic cerebral palsy in humans. They tested the rats at 4 weeks of age using a horizontal ladder test and selected only those with significantly low scores for the study.
They administered SHED intravenously to the selected rats during the chronic phase at 5, 7, and 9 weeks of age—roughly equivalent to pre-adolescence in humans.
The researchers compared motor and learning functions between SHED-treated and untreated rats. In the horizontal ladder test, where rats crossed a ladder with irregularly spaced rungs, the SHED group had a significantly lower number of slips than the control group at four months.
In the cylinder test, which measures forelimb asymmetry, the SHED group relied more on the impaired forelimb than the control group. In the shuttle avoidance test, the SHED group demonstrated significantly better avoidance rates in later sessions, suggesting improved learning and memory.
Using quantum dot-labeled SHED with in vivo imaging, the researchers tracked the cells’ migration and biodistribution, confirming that they migrated to the brain.
Cell culture experiments
The research team also performed cell culture experiments to evaluate SHED by comparing it with other stem cell types, such as bone marrow mesenchymal stromal cells and dermal fibroblasts.
In non-contact co-culture experiments, SHED promoted neural stem cell proliferation more effectively than the other cell types. The researchers attribute this effect to SHED’s high secretion of hepatocyte growth factor (HGF).
These results suggest that SHED treatment could improve motor and cognitive impairments in rat models of cerebral palsy, even in the chronic phase. This therapeutic effect appears to occur through the promotion of new nervous tissue growth via HGF and related biological pathways.
Looking ahead
Nagoya University Hospital is conducting a clinical study to evaluate the safety and tolerability of a single intravenous dose of autologous SHED in children with cerebral palsy. Based on the results of this study, the team plans to conduct large-scale trials and long-term follow-up studies to confirm the treatment’s efficacy.
“Our ultimate goal is to establish this approach as a new treatment option for patients with cerebral palsy and their families,” Sato said.
Published in journal: Stem Cell Research & Therapy
Title: Novel stem cell therapy for cerebral palsy using stem cells from human exfoliated deciduous teeth
Authors: Takahiro Kanzawa, Atsuto Onoda, Azusa Okamoto, Xu Yue, Ryoko Shimode, Yukina Takamoto, Sakiko Suzuki, Kazuto Ueda, Ryosuke Miura, Toshihiko Suzuki, Naoki Tajiri, Shinobu Shimizu, Saho Morita, Hiroshi Yukawa, Hiroshi Kohara, Noritaka Fukuda, Yasuyuki Mitani, Hideki Hida, Yoshiyuki Takahashi, and Yoshiaki Sato
Source/Credit: Nagoya University
Reference Number: ns030426_01
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