CC BY-NC-ND 4.0 · Am J Perinatol 2022; 39(16): 1754-1763
DOI: 10.1055/s-0041-1726451
Review Article

Preventing Brain Damage from Hypoxic–Ischemic Encephalopathy in Neonates: Update on Mesenchymal Stromal Cells and Umbilical Cord Blood Cells

Makoto Nabetani
1   Department of Pediatrics, Yodogawa Christian Hospital, Osaka, Japan
2   Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Haruo Shintaku
3   Department of Pediatrics, Faculty of Medicine, Osaka City University, Osaka, Japan
› Author Affiliations
Funding H.S. received public grant from Japan Agency for Medical Research and Development for autologous UCB stem cell therapy for neonatal HIE in Japan.


Neonatal hypoxic–ischemic encephalopathy (HIE) causes permanent motor deficit “cerebral palsy (CP),” and may result in significant disability and death. Therapeutic hypothermia (TH) had been established as the first effective therapy for neonates with HIE; however, TH must be initiated within the first 6 hours after birth, and the number needed to treat is from 9 to 11 to prevent brain damage from HIE. Therefore, additional therapies for HIE are highly needed. In this review, we provide an introduction on the mechanisms of HIE cascade and how TH and cell therapies such as umbilical cord blood cells and mesenchymal stromal cells (MSCs), especially umbilical cord-derived MSCs (UC-MSCs), may protect the brain in newborns, and discuss recent progress in regenerative therapies using UC-MSCs for neurological disorders.

The brain damage process “HIE cascade” was divided into six stages: (1) energy depletion, (2) impairment of microglia, (3) inflammation, (4) excitotoxity, (5) oxidative stress, and (6) apoptosis in capillary, glia, synapse and/or neuron. The authors showed recent 13 clinical trials using UC-MSCs for neurological disorders.

The authors suggest that the next step will include reaching a consensus on cell therapies for HIE and establishment of effective protocols for cell therapy for HIE.

Key Points

  • This study includes new insights about cell therapy for neonatal HIE and CP in schema.

  • This study shows precise mechanism of neonatal HIE cascade.

  • The mechanism of cell therapy by comparing umbilical cord blood stem cell with MSC is shown.

  • The review of recent clinical trials of UC-MSC is shown.

Authors' Contributions

M.N. and H.S conceptualized the manuscript; T.M. was involved in methodology and software; T.M. and H.S. were involved in validation. M.N. wrote the original draft and was involved in formal analysis and investigation, and manuscript preparation, review, and editing. H.S. was involved in supervision, project administration, and funding acquisition. All authors have read and agreed to the published version of the manuscript.

Publication History

Received: 05 October 2020

Accepted: 11 February 2021

Article published online:
14 April 2021

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