Umbilical Cord Blood-Derived Cell Therapy for Perinatal Brain Injury: A Systematic Review &amp; Meta-Analysis of Preclinical Studies

Nguyen, Timothy; Purcell, Elisha; Smith, Madeleine J.; Penny, Tayla; Paton, Madison C. B.; Zhou, Lindsay; Jenkin, Graham; Miller, Suzanne L.; McDonald, Courtney; Malhotra, Atul

doi:10.3390/ijms24054351

Cited by 10 publications

(7 citation statements)

References 93 publications

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“…On the basis of our findings in preterm sheep, we suggest that caution should be taken in future studies if UCB cells are to be used in preterm infants as an early therapeutic intervention strategy for preterm brain injury. The growing interest in, feasibility and safety profile of UCB cells for preterm infants encourages their early administration to optimise neuroprotection [ 4 , 9 , 48 , 49 ], however in these studies “early” treatment is still > 12 h post initial insult. Notwithstanding the other morbidities that are likely to occur in preterm infants, the majority of preterm infants require respiratory support for varying periods of time.…”

Section: Discussionmentioning

confidence: 99%

Early administration of umbilical cord blood cells following brief high tidal volume ventilation in preterm sheep: a cautionary tale

Tran,

Penny,

Chan

et al. 2024

J Neuroinflammation

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Background Umbilical cord blood (UCB) cells are a promising treatment for preterm brain injury. Access to allogeneic sources of UCB cells offer the potential for early administration to optimise their therapeutic capacities. As preterm infants often require ventilatory support, which can contribute to preterm brain injury, we investigated the efficacy of early UCB cell administration following ventilation to reduce white matter inflammation and injury. Methods Preterm fetal sheep (0.85 gestation) were randomly allocated to no ventilation (SHAM; n = 5) or 15 min ex utero high tidal volume ventilation. One hour following ventilation, fetuses were randomly allocated to i.v. administration of saline (VENT; n = 7) or allogeneic term-derived UCB cells (24.5 ± 5.0 million cells/kg; VENT + UCB; n = 7). Twenty-four hours after ventilation, lambs were delivered for magnetic resonance imaging and post-mortem brain tissue collected. Arterial plasma was collected throughout the experiment for cytokine analyses. To further investigate the results from the in vivo study, mononuclear cells (MNCs) isolated from human UCB were subjected to in vitro cytokine-spiked culture medium (TNFα and/or IFNγ; 10 ng/mL; n = 3/group) for 16 h then supernatant and cells collected for protein and mRNA assessments respectively. Results In VENT + UCB lambs, systemic IFNγ levels increased and by 24 h, there was white matter neuroglial activation, vascular damage, reduced oligodendrocytes, and increased average, radial and mean diffusivity compared to VENT and SHAM. No evidence of white matter inflammation or injury was present in VENT lambs, except for mRNA downregulation of OCLN and CLDN1 compared to SHAM. In vitro, MNCs subjected to TNFα and/or IFNγ displayed both pro- and anti-inflammatory characteristics indicated by changes in cytokine (IL-18 & IL-10) and growth factor (BDNF & VEGF) gene and protein expression compared to controls. Conclusions UCB cells administered early after brief high tidal volume ventilation in preterm fetal sheep causes white matter injury, and the mechanisms underlying these changes are likely dysregulated responses of the UCB cells to the degree of injury/inflammation already present. If immunomodulatory therapies such as UCB cells are to become a therapeutic strategy for preterm brain injury, especially after ventilation, our study suggests that the inflammatory state of the preterm infant should be considered when timing UCB cells administration.

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Section: Discussionmentioning

confidence: 99%

Early administration of umbilical cord blood cells following brief high tidal volume ventilation in preterm sheep: a cautionary tale

Tran,

Penny,

Chan

et al. 2024

J Neuroinflammation

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“…A systematic meta-analysis of 55 studies demonstrated that UCB-derived cell therapy was an efficacious treatment in pre-clinical models of perinatal brain injury. 55 UCB-derived cells were thought to exert their neuroprotective effects by significantly reducing microglial activation, astrogliosis, apoptosis, neuroinflammation and so reducing infarct size, and improving numbers of neurons and oligodendrocytes and overall motor function. Further analysis suggested that these therapies may be more efficacious in IVH models compared to models of hypoxia ischemia and when given through local routes as compared to systemic routes.…”

Section: Cord Blood-derived Cell Therapiesmentioning

confidence: 99%

Advances in neonatal cell therapies: Proceedings of the First Neonatal Cell Therapies Symposium (2022)

et al. 2023

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Despite considerable advances, there is a need to improve the outcomes of newborn infants, especially related to prematurity, encephalopathy and other conditions. In principle, cell therapies have the potential to protect, repair, or sometimes regenerate vital tissues; and improve or sustain organ function. In this review, we present highlights from the First Neonatal Cell Therapies Symposium (2022). Cells tested in preclinical and clinical studies include mesenchymal stromal cells from various sources, umbilical cord blood and cord tissue derived cells, and placental tissue and membrane derived cells. Overall, most preclinical studies suggest potential for benefit, but many of the cells tested were not adequately defined, and the optimal cell type, timing, frequency, cell dose or the most effective protocols for the targeted conditions is not known. There is as yet no clinical evidence for benefit, but several early phase clinical trials are now assessing safety in newborn babies. We discuss parental perspectives on their involvement in these trials, and lessons learnt from previous translational work of promising neonatal therapies. Finally, we make a call to the many research groups around the world working in this exciting yet complex field, to work together to make substantial and timely progress to address the knowledge gaps and move the field forward. Impact Survival of preterm and sick newborn infants is improving, but they continue to be at high risk of many systemic and organ-specific complications. Cell therapies show promising results in preclinical models of various neonatal conditions and early phase clinical trials have been completed or underway. Progress on the potential utility of cell therapies for neonatal conditions, parental perspectives and translational aspects are discussed in this paper.

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“…One of the most studied sources of cells for treating neonatal brain disorders is the umbilical cord blood, which contains hematopoietic stem/progenitor cells, endothelial progenitor cells, monocytes, mesenchymal stem cells, and lymphocytes, among other circulating mononuclear cells. Multiple studies have demonstrated that umbilical cord blood cells protect the brain in HIE and NAIS 123–126 …”

Section: Potential Treatments For Hie and Nais Focused On Monocytesmentioning

confidence: 99%

“…Multiple studies have demonstrated that umbilical cord blood cells protect the brain in HIE and NAIS. [123][124][125][126] Currently, it is unknown which cell types present in the umbilical cord blood are necessary for the beneficial effects observed in these models. Saha et al 127 demonstrated that CD14 + monocytes from the umbilical cord blood protected neurons and reduced glial activation in organotypic forebrain slice cultures subjected to oxygen-glucose deprivation.…”

Section: Cell-based Therapiesmentioning

confidence: 99%

Monocytes in neonatal stroke and hypoxic‐ischemic encephalopathy: Pathophysiological mechanisms and therapeutic possibilities

Pimentel‐Coelho

2023

Neuroprotection

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Neonatal arterial ischemic stroke (NAIS) and neonatal hypoxic‐ischemic encephalopathy (HIE) are common causes of neurological impairments in infants, for which treatment options are very limited. NAIS and HIE induce an innate immune response that involves the recruitment of peripheral immune cells, including monocytes, into the brain. Monocytes and monocyte‐derived cells have the potential to contribute to both harmful and beneficial pathophysiological processes, such as neuroinflammation and brain repair, but their roles in NAIS and HIE remain poorly understood. Furthermore, recent evidence indicates that monocyte‐derived macrophages can persist in the brain for several months following NAIS and HIE in mice, with possible long‐lasting consequences that are still unknown. This review provides a comprehensive overview of the mechanisms of monocyte infiltration and their potential functions in the ischemic brain, focusing on HIE and NAIS. Therapeutic strategies targeting monocytes and the possibility of using monocytes for cell‐based therapies are also discussed.

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Umbilical Cord Blood-Derived Cell Therapy for Perinatal Brain Injury: A Systematic Review & Meta-Analysis of Preclinical Studies

Cited by 10 publications

References 93 publications

Early administration of umbilical cord blood cells following brief high tidal volume ventilation in preterm sheep: a cautionary tale

Early administration of umbilical cord blood cells following brief high tidal volume ventilation in preterm sheep: a cautionary tale

Advances in neonatal cell therapies: Proceedings of the First Neonatal Cell Therapies Symposium (2022)

Monocytes in neonatal stroke and hypoxic‐ischemic encephalopathy: Pathophysiological mechanisms and therapeutic possibilities

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