Nagoya University Researchers Advance SHED Therapy for Cerebral Palsy Treatment

A team from Nagoya University Graduate School of Medicine has made headlines with a pioneering study demonstrating that stem cells from human exfoliated deciduous teeth, known as SHED or stem cells from baby teeth, can significantly improve motor function and cognitive abilities in rat models of chronic cerebral palsy (CP). Published in Stem Cell Research & Therapy on January 23, 2026, this research marks the first animal study to show efficacy even after symptoms have fully developed, opening new doors for regenerative medicine in Japan.

The study, led by researchers including Takahiro Kanzawa and corresponding author Yoshiaki Sato from the Department of Pediatrics, used a well-established Rice-Vannucci rat model to simulate hypoxic-ischemic encephalopathy (HIE), the primary cause of CP. Neonatal rats underwent unilateral common carotid artery ligation followed by hypoxia, resulting in one-sided motor impairments mimicking hemiplegic CP. Treatment with intravenous SHED at 1 million cells per dose, administered three times during the chronic phase (5, 7, and 9 weeks old), led to measurable recoveries.

Understanding Cerebral Palsy: A Lifelong Challenge

Cerebral palsy encompasses a group of permanent movement disorders caused by non-progressive brain damage occurring in the developing fetal or infant brain, most commonly from perinatal HIE due to oxygen deprivation and reduced blood flow. Globally, CP affects 2 to 3 per 1,000 live births, with Japan reporting similar rates of around 1.8 to 2.3 per 1,000 live births, translating to thousands of new cases annually. Symptoms include impaired muscle coordination, posture issues, and cognitive delays, with hemiplegic CP—one-sided weakness—being common. Current treatments focus on symptom management through physical therapy, medications, and orthotics, but no cure exists to reverse brain damage, especially in the chronic phase when diagnosis often occurs.

In Japan, where advanced perinatal care has stabilized CP incidence despite declining preterm births, the burden remains high. Nagoya University's work addresses this gap, targeting post-symptomatic intervention when therapeutic hypothermia—the standard acute treatment—is no longer viable.

What Are SHED Stem Cells and Why Baby Teeth?

SHED, or stem cells from human exfoliated deciduous teeth, are mesenchymal stem cells (MSCs) derived from the dental pulp of naturally shed primary (baby) teeth. Unlike embryonic stem cells, SHED collection is ethical and non-invasive—teeth discarded after falling out between ages 6-12 provide a rich source. These cells exhibit high proliferation rates, multipotency (ability to differentiate into bone, cartilage, neurons), and robust secretion of trophic factors like hepatocyte growth factor (HGF), which promote tissue repair without direct cell replacement.

Compared to bone marrow MSCs (BMMSCs) or adipose-derived stem cells, SHED secrete higher levels of neuroprotective factors such as HGF, stromal-derived factor-1 (SDF-1), and brain-derived neurotrophic factor (BDNF). This paracrine effect—releasing signaling molecules—underpins their therapeutic potential, reducing inflammation, enhancing angiogenesis, and stimulating endogenous neural stem cell (NSC) proliferation. For pediatric applications like CP, autologous SHED (from the patient's own teeth) minimize rejection risks.

Detailed Methods: Simulating Chronic CP in Rats

The Nagoya team induced HIE in postnatal day 7 (P7) Wistar rats via left carotid artery ligation and 60-minute 8% hypoxia at 37°C, per the Rice-Vannucci protocol. At 4 weeks, impaired rats (horizontal ladder gait score <1 SD below sham mean) received SHED (passages 4-7 from Kidswell Bio) or vehicle intravenously. Quantum dot (QD)-labeling tracked migration via IVIS imaging and light-sheet microscopy on cleared brains.

Behavioral assessments included:

• Horizontal ladder test: Fewer slips in SHED group (p<0.001, Cohen's d effect size large).
• Cylinder test: Reduced forelimb asymmetry (p<0.05).
• Shuttle avoidance: Improved learning/memory (higher avoidance rates in later sessions, p<0.01).

Impressive Results: Motor and Cognitive Gains

SHED-treated rats showed robust recovery: at 4 months (16 weeks post-first dose), ladder slips dropped significantly versus controls, indicating better coordination. Cylinder tests revealed balanced forelimb use, and shuttle tests demonstrated enhanced associative learning. Brain histology confirmed increased neurogenesis in subventricular zone (SVZ), dentate gyrus, and striatum (BrdU+/DCX+ cells p<0.001), with sustained NeuN+ neurons in cortex/hippocampus (p<0.001).

QD imaging peaked SHED signal in brain at 24-48 hours, confirming homing. No apoptosis increase (active caspase-3). Proteomics highlighted neurogenesis clusters (enrichment score >2.0).Read the full study here.

Photo by National Institute of Allergy and Infectious Diseases on Unsplash

Unraveling the Mechanisms: HGF and PI3K-Akt Pathway

In vitro, SHED-conditioned medium boosted adult rat NSC proliferation (SOX2+/Ki67+ p<0.0001) more than BMMSCs or fibroblasts, driven by elevated HGF (ELISA-confirmed, p<0.001). HGF neutralization or CRISPR-KO SHED abolished effects, rescued by recombinant HGF. RNA-seq revealed PI3K-Akt pathway activation (p-Akt Ser473 upregulation, SOX2/p-Akt+ cells p<0.001), inhibiting cell cycle inhibitor p27Kip1 to promote NSC division.

This paracrine mechanism fosters endogenous repair, ideal for chronic CP where direct engraftment is limited.

SHED Advantages and Comparisons in Regenerative Therapy

SHED outperform traditional MSCs: easier autologous harvest (no surgery), higher trophic secretion, lower immunogenicity. Other CP trials use cord blood or BMMSCs (e.g., Duke's cord blood studies showing motor gains), but SHED avoid ethical issues and expand readily. In Japan, prior dental pulp studies targeted spinal cord injury.

Nagoya's collaboration with S-Quatre (Kidswell Bio subsidiary) accelerates translation, with Phase I interim data (Nov 2025) confirming safety in 3 pediatric CP patients—no adverse events, hints of motor improvement.Nagoya University announcement.

Nagoya University: A Hub for Stem Cell Innovation in Japan

Nagoya University, a top Japanese national university with six Nobel laureates since 2001, excels in regenerative medicine. Its Graduate School of Medicine hosts labs in functional regenerative medicine, developmental neurobiology, and cell physiology, fostering interdisciplinary stem cell research. Japan’s AMED funding supports such programs, positioning Nagoya as a leader.

For aspiring researchers, opportunities abound in higher ed research jobs at institutions like Nagoya, advancing fields like SHED therapy.

Challenges, Limitations, and Path Forward

• Xenogeneic model limitations (human-rat differences); future humanized studies needed.
• Small omics n, unequal groups (stats adjusted).
• HGF tumorigenic risk; requires safety trials.
• Dose optimization, long-term differentiation tracking.

Phase II trials planned post-Phase I (Nagoya Hospital, autologous SHED IV). Japan's regenerative medicine laws expedite approvals. Global CP trials (e.g., cord blood) report 20-30% motor gains; SHED could exceed via chronic efficacy.

Implications for Japanese Higher Education and Global Health

This breakthrough underscores Japan's higher ed prowess in biotech, with Nagoya driving iPS cell legacies (Shinya Yamanaka, Nobel 2012). Collaborations like S-Quatre boost translation. For patients, SHED offers hope: accessible, safe, potent. Researchers eyeing Japan university jobs or academic CV tips will find fertile ground.

Stakeholders—parents, clinicians, policymakers—anticipate trials expanding access. Ethical sourcing aligns with Japan's stem cell ethics.

Photo by Bioscience Image Library by Fayette Reynolds on Unsplash

Future Outlook: From Bench to Bedside

Nagoya's SHED therapy could redefine CP management, complementing therapies. Large-scale trials, standardization (HGF as CQA), and global partnerships loom. As Clinical Professor Sato states: "Our ultimate goal is to establish this as a new treatment option for CP patients and families."

Explore Rate My Professor for Nagoya educators, higher ed jobs in regenerative fields, or career advice. University jobs in Japan await innovators.