Stem Cell Therapy for Neonatal Hypoxic-Ischemic Encephalopathy: A Systematic Review of Preclinical Studies

Serrenho, Inês; Rosado, Miguel; Dinis, Alexandra; Cardoso, Carla M. P.; Grãos, Mário; Manadas, Bruno; Baltazar, Graça

doi:10.3390/ijms22063142

Cited by 44 publications

(35 citation statements)

References 122 publications

(354 reference statements)

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“…Stem cell therapy is outside the scope of this review. Serrenho I et al (2021) provides a systematic review of preclinical studies done on stem cell therapy for neonatal HIE [ 111 ]. Eighty percent of these studies reported a significant improvement of cognitive and/or sensorimotor function, as well as decreased brain damage.…”

Section: Discussionmentioning

confidence: 99%

New possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy

et al. 2021

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Around 0.75 million babies worldwide suffer from moderate or severe hypoxic-ischemic encephalopathy (HIE) each year resulting in around 400,000 babies with neurodevelopmental impairment. In 2010, neonatal HIE was associated with 2.4% of the total Global Burden of Disease. Therapeutic hypothermia (TH), a treatment that is now standard of care in high-income countries, provides proof of concept that strategies that aim to improve neurodevelopment are not only possible but can also be implemented to clinical practice. While TH is beneficial, neonates with moderate or severe HIE treated with TH still experience devastating complications: 48% (range: 44–53) combined death or moderate/severe disability. There is a concern that TH may not be effective in low- and middle-income countries. Therapies that further improve outcomes are desperately needed, and in high-income countries, they must be tested in conjunction with TH. We have in this review focussed on pharmacological treatment options (e.g. erythropoietin, allopurinol, melatonin, cannabidiol, exendin-4/exenatide). Erythropoietin and allopurinol show promise and are progressing towards the clinic with ongoing definitive phase 3 randomised placebo-controlled trials. However, there remain global challenges for the next decade. Conclusion: There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials to avoid exposure to harmful medications or abandoning putative treatments. What is Known:• Therapeutic hypothermia is beneficial in neonatal hypoxic-ischemic encephalopathy.• Neonates with moderate or severe hypoxic-ischemic encephalopathy treated with therapeutic hypothermia still experience severe sequelae. What is New:• Erythropoietin, allopurinol, melatonin, cannabidiol, and exendin-4/exenatide show promise in conjunction with therapeutic hypothermia.• There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials.

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Section: Discussionmentioning

confidence: 99%

New possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy

et al. 2021

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“…4). SCs from neonatal tissue may display improved features in comparison to those isolated from adults, for instance MSCs derived from neonatal tissue display improved capacity for proliferation, expansion and engraftment in comparison to adult MSCs [183]. Cells from birth related tissue (UC, placenta) also raise no ethical issues; practically, they can be easily harvested and banked and are therefore rapidly available for both autologous or allogenic use in human patients.…”

Section: General Considerations On Scs Used In Clinical Trialsmentioning

confidence: 99%

Microglia and Stem-Cell Mediated Neuroprotection after Neonatal Hypoxia-Ischemia

Brégère

Schwendele

Radanovic

et al. 2021

Stem Cell Rev and Rep

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Neonatal hypoxia-ischemia encephalopathy (HIE) refers to a brain injury in term infants that can lead to death or lifelong neurological deficits such as cerebral palsy (CP). The pathogenesis of this disease involves multiple cellular and molecular events, notably a neuroinflammatory response driven partly by microglia, the brain resident macrophages. Treatment options are currently very limited, but stem cell (SC) therapy holds promise, as beneficial outcomes are reported in animal studies and to a lesser degree in human trials. Among putative mechanisms of action, immunomodulation is considered a major contributor to SC associated benefits. The goal of this review is to examine whether microglia is a cellular target of SC-mediated immunomodulation and whether the recruitment of microglia is linked to brain repair. We will first provide an overview on microglial activation in the rodent model of neonatal HI, and highlight its sensitivity to developmental age. Two complementary questions are then addressed: (i) do immune-related treatments impact microglia and provide neuroprotection, (ii) does stem cell treatment modulates microglia? Finally, the immune-related findings in patients enrolled in SC based clinical trials are discussed. Our review points to an impact of SCs on the microglial phenotype, but heterogeneity in experimental designs and methodological limitations hamper our understanding of a potential contribution of microglia to SC associated benefits. Thorough analyses of the microglial phenotype are warranted to better address the relevance of the neuroimmune crosstalk in brain repair and improve or advance the development of SC protocols in humans. Graphical abstract

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“…Stem cell therapy is emerging as a promising therapeutic approach for various diseases, including HIBD, due to their abilities to self-renew and differentiate [ 7 ]. Mesenchymal stem cells (MSCs) are a subset of multipotent stem cells that are present in both adult and neonatal tissues and fluids, such as bone marrow, placenta, adipose tissue, umbilical cord tissue, and umbilical cord blood.…”

Section: Introductionmentioning

confidence: 99%

Bone marrow mesenchymal stem cells overexpressing hepatocyte growth factor ameliorate hypoxic–ischemic brain damage in neonatal rats

Zeng

et al. 2021

Translational Neuroscience

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Objectives Hypoxic–ischemic brain damage (HIBD) is a major cause of brain injury in neonates. Bone marrow mesenchymal stem cells (BMSCs) show therapeutic potential for HIBD, and genetic modification may enhance their neuroprotective effects. The goal of this study was to investigate the neuroprotective effects of hepatocyte growth factor (HGF)-overexpressing BMSCs (BMSCs-HGF) against HIBD and their underlying mechanisms. Methods: BMSCs were transfected with HGF using adenoviral vectors. HIBD models were established and then BMSCs were transplanted into the brains of HIBD rats via intraventricular injection. 2,3,5-Triphenyltetrazolium chloride (TTC) staining was used to measure cerebral infarction volumes. In vitro, primary cultured cortical neurons were co-cultured with BMSCs in a Transwell plate system. Oxygen–glucose deprivation (OGD) was applied to imitate hypoxic–ischemic insult, and PD98059 was added to the culture medium to block the phosphorylation of extracellular signal-regulated kinase (ERK). Cell apoptosis was determined using TUNEL staining. The expression of HGF was measured by immunofluorescence, real-time quantitative PCR (RT-qPCR), and western blots. The expression of phosphorylated ERK (p-ERK) and B-cell lymphoma-2 (Bcl-2) was measured by western blots. Results HGF-gene transfection promoted BMSC proliferation. Moreover, BMSCs-HGF decreased HIBD-induced cerebral infarction volumes and enhanced the protective effects of the BMSCs against HIBD. BMSCs-HGF also increased expression of HGF, p-ERK, and Bcl-2 in brain tissues. In vitro, BMSC-HGF protected neurons against OGD-induced apoptosis. Inhibition of ERK phosphorylation abolished the neuroprotective effect of BMSCs-HGF against OGD. Conclusions BMSCs-HGF is a potential treatment for HIBD and that the ERK/Bcl-2 pathway is involved in the underlying neuroprotective mechanism.

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Stem Cell Therapy for Neonatal Hypoxic-Ischemic Encephalopathy: A Systematic Review of Preclinical Studies

Cited by 44 publications

References 122 publications

New possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy

New possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy

Microglia and Stem-Cell Mediated Neuroprotection after Neonatal Hypoxia-Ischemia

Bone marrow mesenchymal stem cells overexpressing hepatocyte growth factor ameliorate hypoxic–ischemic brain damage in neonatal rats

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