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Zhang M, Wang H, He Y, Li W, Chen H, Zhang X, Chen Q, Yang C, Luo M, Zhang B, Tang J, Mu D. Effects and mechanisms of breastmilk stem cells in the treatment of white matter injury in newborn rats. Stem Cell Res Ther 2025; 16:124. [PMID: 40055828 PMCID: PMC11887140 DOI: 10.1186/s13287-025-04257-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 02/27/2025] [Indexed: 05/13/2025] Open
Abstract
BACKGROUND Breastmilk stem cells (BSCs) have been reported to have potential benefits for infants. However, whether the BSCs could improve brain injury is unknown. A culture system for BSCs was established, and the roles of BSCs in treating white matter injury (WMI) were investigated in our study. METHODS Breastmilk samples were collected from healthy lactating women between days 1 and 5 after delivery. The BSCs were cultured in a specialized culture medium and then characterized through flow cytometry and immunofluorescence methods. A rat model with WMI was established by ligating the right carotid artery of Sprague-Dawley rats at postnatal day 3 (P3) and exposing the rats to 6% hypoxia for 2 h. Rats were categorized into sham, WMI with breastmilk cell (WMI + BC), and WMI with (WMI + NS) groups. In the WMI + BC group, 5 µL BCs (1 × 106) was injected into the lateral ventricle 24 h post-modeling. Four different stages of oligodendrocyte (OL) markers were observed. Long-term neurobehavioral evaluations were conducted using the Morris water maze test. The inflammatory cytokines and proportion of proinflammatory microglial cells were detected to study the mechanisms of BSC treatment. RESULTS The isolated BSCs expressed mesenchymal stem cell-positive markers, including CD105, CD73, CD29, CD166, CD44, and CD90. Meanwhile, the mesenchymal stem cell-negative markers, including HLA-DR, CD45, and CD79a, were also found in BSCs. The BSCs did not express pluripotent stem cell markers, including SOX2, Nanog, OCT4, SSEA4, and TRA-1-60. Immunofluorescence detection showed that BSCs expressed neural stem/progenitor cell markers, including Vimentin, Nestin, and A2B5. Following BSC treatment, pathological improvements were observed in WMI. The expressions of mature OLs markers myelin basic protein and myelin-associated glycoprotein were increased in the corpus callosum and periventricular areas. Meanwhile, the numbers of myelin sheath increased, and learning and memory abilities improved. Furthermore, a decrease in B7-2+/Iba1 + proinflammatory microglia and an increase in CD206+/Iba1 + anti-inflammatory microglia were observed. The mRNA expressions of proinflammatory factors (Il1b, Il6, Ifng, and Tnfa) and anti-inflammatory factors (Arg1 and Tgfb) decreased and increased, respectively. CONCLUSION Our findings suggest that BSCs can improve the maturation of OLs following WMI in newborn rats. The mechanisms may be attributed to the reduced proinflammatory microglia cells and factors as well as the increased anti-inflammatory microglia cells and factors.
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Affiliation(s)
- Meng Zhang
- Department of Pediatrics, West China Second Hospital, Sichuan University, No. 20, Section 3, Renmin South Road, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, No. 17, Section 3, Renmin South Road, Chengdu, Sichuan, 610041, China
| | - Haoran Wang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, No. 17, Section 3, Renmin South Road, Chengdu, Sichuan, 610041, China
| | - Yang He
- Department of Pediatrics, West China Second Hospital, Sichuan University, No. 20, Section 3, Renmin South Road, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, No. 17, Section 3, Renmin South Road, Chengdu, Sichuan, 610041, China
| | - Wenxing Li
- Department of Pediatrics, West China Second Hospital, Sichuan University, No. 20, Section 3, Renmin South Road, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, No. 17, Section 3, Renmin South Road, Chengdu, Sichuan, 610041, China
| | - Hongju Chen
- Department of Pediatrics, West China Second Hospital, Sichuan University, No. 20, Section 3, Renmin South Road, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, No. 17, Section 3, Renmin South Road, Chengdu, Sichuan, 610041, China
| | - Xinyu Zhang
- Department of Pediatrics, West China Second Hospital, Sichuan University, No. 20, Section 3, Renmin South Road, Chengdu, 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, No. 17, Section 3, Renmin South Road, Chengdu, Sichuan, 610041, China
| | - Qiang Chen
- Sichuan Cord Blood Bank, Chengdu, 610037, China
| | - Chao Yang
- Sichuan Cord Blood Bank, Chengdu, 610037, China
| | - Maowen Luo
- Sichuan Cord Blood Bank, Chengdu, 610037, China
| | - Bo Zhang
- Sichuan Cord Blood Bank, Chengdu, 610037, China
| | - Jun Tang
- Department of Pediatrics, West China Second Hospital, Sichuan University, No. 20, Section 3, Renmin South Road, Chengdu, 610041, China.
| | - Dezhi Mu
- Department of Pediatrics, West China Second Hospital, Sichuan University, No. 20, Section 3, Renmin South Road, Chengdu, 610041, China.
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, No. 17, Section 3, Renmin South Road, Chengdu, Sichuan, 610041, China.
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Yang M, Wang K, Liu B, Shen Y, Liu G. Hypoxic-Ischemic Encephalopathy: Pathogenesis and Promising Therapies. Mol Neurobiol 2025; 62:2105-2122. [PMID: 39073530 DOI: 10.1007/s12035-024-04398-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024]
Abstract
Hypoxic-ischemic encephalopathy (HIE) is a brain lesion caused by inadequate blood supply and oxygen deprivation, often occurring in neonates. It has emerged as a grave complication of neonatal asphyxia, leading to chronic neurological damage. Nevertheless, the precise pathophysiological mechanisms underlying HIE are not entirely understood. This paper aims to comprehensively elucidate the contributions of hypoxia-ischemia, reperfusion injury, inflammation, oxidative stress, mitochondrial dysfunction, excitotoxicity, ferroptosis, endoplasmic reticulum stress, and apoptosis to the onset and progression of HIE. Currently, hypothermia therapy stands as the sole standard treatment for neonatal HIE, albeit providing only partial neuroprotection. Drug therapy and stem cell therapy have been explored in the treatment of HIE, exhibiting certain neuroprotective effects. Employing drug therapy or stem cell therapy as adjunctive treatments to hypothermia therapy holds great significance. This article presents a systematic review of the pathogenesis and treatment strategies of HIE, with the goal of enhancing the effect of treatment and improving the quality of life for HIE patients.
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Affiliation(s)
- Mingming Yang
- Department of Pediatrics, Binhai County People's Hospital, Yancheng, Jiangsu Province, 224500, P. R. China
| | - Kexin Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Boya Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Yuntian Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China.
| | - Guangliang Liu
- Department of Pediatrics, Binhai County People's Hospital, Yancheng, Jiangsu Province, 224500, P. R. China.
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Gallipoli A, Unger S, El Shahed A, Fan CPS, Signorile M, Wilson D, Hoban R. Outcomes after intranasal human milk therapy in preterm infants with intraventricular hemorrhage. J Perinatol 2025; 45:202-207. [PMID: 39384614 DOI: 10.1038/s41372-024-02147-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 09/27/2024] [Accepted: 10/01/2024] [Indexed: 10/11/2024]
Abstract
OBJECTIVE Intraventricular hemorrhage (IVH) is a common cause of brain injury in preterm infants. Fresh human milk (HM) contains stem cells (SCs) that could potentially be delivered via intranasal HM (IHM). In this IHM pilot study, we describe outcomes. STUDY DESIGN Infants <33 weeks gestation with IVH were given IHM until maximum 28 days of age. Short-term neurologic outcomes and follow-up testing were compared to historic HM-fed infants. Longitudinal outcomes were plotted using linear mixed models. Weighted G-computation quantified treatment effects. Propensity score models calculated inverse probability weights for IVH grade, gestational age, and sex. RESULT 37 infants (35.1% grade 3-4 IVH) were compared to 191 historic controls (17.8% grade 3-4 IVH). Post-hemorrhagic ventricular dilatation was common (25.7% IHM patients). Most weighted outcomes, although not significant, favored IHM at 4-12 and 18 months corrected age. CONCLUSION This phase 1 study suggests powered trials of IHM for brain injury are needed. CLINICAL TRIAL REGISTRY NAME: clinicaltrials.gov identifier NCT04225286.
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Affiliation(s)
- Alessia Gallipoli
- Division of Neonatology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Sharon Unger
- Department of Paediatrics, Izaak Walton Killam Hospital, Halifax, NS, Canada
| | - Amr El Shahed
- Division of Neonatology, The Hospital for Sick Children, Toronto, ON, Canada
- University of Toronto, Toronto, ON, Canada
| | - Chun-Po Steve Fan
- Ted Rogers Computational Program, Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada
| | - Marisa Signorile
- Ted Rogers Computational Program, Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada
| | - Diane Wilson
- Division of Neonatology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Rebecca Hoban
- Division of Neonatology, The Hospital for Sick Children, Toronto, ON, Canada.
- Division of Neonatology, Seattle Children's Hospital, Seattle, WA, USA.
- University of Washington, Seattle, WA, USA.
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Hoban R, Gallipoli A, Signorile M, Mander P, Gauthier-Fisher A, Librach C, Wilson D, Unger S. Feasibility of intranasal human milk as stem cell therapy in preterm infants with intraventricular hemorrhage. J Perinatol 2024; 44:1652-1657. [PMID: 38688998 DOI: 10.1038/s41372-024-01982-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 04/15/2024] [Accepted: 04/17/2024] [Indexed: 05/02/2024]
Abstract
OBJECTIVE Intraventricular hemorrhage (IVH) is a common cause of preterm brain injury. Fresh parent's own milk (POM) contains pluripotent stem cells (SCs) that produce neuronal cells in-vitro. The permeable neonatal blood brain barrier potentially allows SC delivery. We performed the first prospective trial (clinicaltrials.gov NCT04225286) of feasibility of intranasal POM (IPOM) in preterm infants with IVH and described SC content of POM samples. STUDY DESIGN 37 Infants (mean gestation 27.7 ± 2.6 weeks, birthweight 1030 ± 320 g) with IVH (35.1% grade IV) were recruited from two tertiary Toronto NICUs. IPOM was given ideally twice daily until 28 days of age. Tolerance and adverse reactions were collected and 162 administering providers surveyed. RESULTS There were no major adverse reactions. Provider surveys suggested acceptability, although potential provider and subject stress requires further study. Milk cell analysis suggests wide variability between parents. CONCLUSIONS This phase 1 study demonstrated IPOM was tolerated and feasible in preterm infants.
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Affiliation(s)
- Rebecca Hoban
- Division of Neonatology, The Hospital for Sick Children/University of Toronto, Toronto, ON, Canada.
- Division of Neonatology, University of Washington, Seattle, WA, USA.
| | - Alessia Gallipoli
- Division of Neonatology, The Hospital for Sick Children/University of Toronto, Toronto, ON, Canada
| | - Marisa Signorile
- Ted Rogers Computational Program, Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada
| | | | | | - Clifford Librach
- CReATe Fertility Centre, Toronto, ON, Canada
- Department of Obstetrics and Gynecology, IMS and Physiology, University of Toronto, Toronto, ON, Canada
- Sunnybrook Research Institute, Toronto, ON, Canada
| | - Diane Wilson
- Division of Neonatology, The Hospital for Sick Children/University of Toronto, Toronto, ON, Canada
| | - Sharon Unger
- Department of Paediatrics, Izaak Walton Killam Hospital, Halifax, NS, Canada
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Xiao QX, Geng MJ, Sun YF, Pi Y, Xiong LL. Stem Cell Therapy in Neonatal Hypoxic-Ischemic Encephalopathy and Cerebral Palsy: a Bibliometric Analysis and New Strategy. Mol Neurobiol 2024; 61:4538-4564. [PMID: 38102517 DOI: 10.1007/s12035-023-03848-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 11/15/2023] [Indexed: 12/17/2023]
Abstract
The aim of this study was to identify related scientific outputs and emerging topics of stem cells in neonatal hypoxic-ischemic encephalopathy (NHIE) and cerebral palsy (CP) through bibliometrics and literature review. All relevant publications on stem cell therapy for NHIE and CP were screened from websites and analyzed research trends. VOSviewer and CiteSpace were applied to visualize and quantitatively analyze the published literature to provide objective presentation and prediction. In addition, the clinical trials, published articles, and projects of the National Natural Science Foundation of China associated with stem cell therapy for NHIE and CP were summarized. A total of 294 publications were associated with stem cell therapy for NHIE and CP. Most publications and citations came from the USA and China. Monash University and University Medical Center Utrecht produced the most publications. Pediatric research published the most studies on stem cell therapy for NHIE and CP. Heijnen C and Kavelaars A published the most articles. Cluster analyses show that current research trend is more inclined toward the repair mechanism and clinical translation of stem cell therapy for NHIE and CP. By summarizing various studies of stem cells in NHIE and CP, it is indicated that this research direction is a hot topic at present. Furthermore, organoid transplantation, as an emerging and new therapeutic approach, brings new hope for the treatment of NHIE and CP. This study comprehensively summarized and analyzed the research trend of global stem cell therapy for NHIE and CP. It has shown a marked increase in stem cell therapy for NHIE and CP research. In the future, more efforts will be made on exploring stem cell or organoid therapy for NHIE and CP and more valuable related mechanisms of action to achieve clinical translation as soon as possible.
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Affiliation(s)
- Qiu-Xia Xiao
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Min-Jian Geng
- Department of Anesthesiology, Nanchong Central Hospital, Nanchong, 637000, Sichuan, China
| | - Yi-Fei Sun
- Institute of Neurological Disease, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yu Pi
- Department of Anesthesiology, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Liu-Lin Xiong
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, Guizhou, China.
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Maïza A, Hamoudi R, Mabondzo A. Targeting the Multiple Complex Processes of Hypoxia-Ischemia to Achieve Neuroprotection. Int J Mol Sci 2024; 25:5449. [PMID: 38791487 PMCID: PMC11121719 DOI: 10.3390/ijms25105449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 05/06/2024] [Accepted: 05/12/2024] [Indexed: 05/26/2024] Open
Abstract
Hypoxic-ischemic encephalopathy (HIE) is a major cause of newborn brain damage stemming from a lack of oxygenated blood flow in the neonatal period. Twenty-five to fifty percent of asphyxiated infants who develop HIE die in the neonatal period, and about sixty percent of survivors develop long-term neurological disabilities. From the first minutes to months after the injury, a cascade of events occurs, leading to blood-brain barrier (BBB) opening, neuronal death and inflammation. To date, the only approach proposed in some cases is therapeutic hypothermia (TH). Unfortunately, TH is only partially protective and is not applicable to all neonates. This review synthesizes current knowledge on the basic molecular mechanisms of brain damage in hypoxia-ischemia (HI) and on the different therapeutic strategies in HI that have been used and explores a major limitation of unsuccessful therapeutic approaches.
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Affiliation(s)
- Auriane Maïza
- CEA, DMTS, SPI, Neurovascular Unit Research & Therapeutic Innovation Laboratory, Paris-Saclay University, CEDEX 91191 Gif-sur-Yvette, France;
| | - Rifat Hamoudi
- Center of Excellence of Precision Medicine, Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates;
- College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
- Division of Surgery and Interventional Science, University College London, London NW3 2PF, UK
| | - Aloïse Mabondzo
- CEA, DMTS, SPI, Neurovascular Unit Research & Therapeutic Innovation Laboratory, Paris-Saclay University, CEDEX 91191 Gif-sur-Yvette, France;
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Ranjan AK, Gulati A. Advances in Therapies to Treat Neonatal Hypoxic-Ischemic Encephalopathy. J Clin Med 2023; 12:6653. [PMID: 37892791 PMCID: PMC10607511 DOI: 10.3390/jcm12206653] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/17/2023] [Accepted: 10/18/2023] [Indexed: 10/29/2023] Open
Abstract
Neonatal hypoxic-ischemic encephalopathy (HIE) is a condition that results in brain damage in newborns due to insufficient blood and oxygen supply during or after birth. HIE is a major cause of neurological disability and mortality in newborns, with over one million neonatal deaths occurring annually worldwide. The severity of brain injury and the outcome of HIE depend on several factors, including the cause of oxygen deprivation, brain maturity, regional blood flow, and maternal health conditions. HIE is classified into mild, moderate, and severe categories based on the extent of brain damage and resulting neurological issues. The pathophysiology of HIE involves different phases, including the primary phase, latent phase, secondary phase, and tertiary phase. The primary and secondary phases are characterized by episodes of energy and cell metabolism failures, increased cytotoxicity and apoptosis, and activated microglia and inflammation in the brain. A tertiary phase occurs if the brain injury persists, characterized by reduced neural plasticity and neuronal loss. Understanding the cellular and molecular aspects of the different phases of HIE is crucial for developing new interventions and therapeutics. This review aims to discuss the pathophysiology of HIE, therapeutic hypothermia (TH), the only approved therapy for HIE, ongoing developments of adjuvants for TH, and potential future drugs for HIE.
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Affiliation(s)
- Amaresh K Ranjan
- Research and Development, Pharmazz Inc., Willowbrook, IL 60527, USA
| | - Anil Gulati
- Research and Development, Pharmazz Inc., Willowbrook, IL 60527, USA
- Department of Bioengineering, The University of Illinois at Chicago, Chicago, IL 60607, USA
- College of Pharmacy, Midwestern University, Downers Grove, IL 60515, USA
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Huang F, He Y, Zhang M, Luo K, Li J, Li J, Zhang X, Dong X, Tang J. Progress in Research on Stem Cells in Neonatal Refractory Diseases. J Pers Med 2023; 13:1281. [PMID: 37623531 PMCID: PMC10455340 DOI: 10.3390/jpm13081281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/03/2023] [Accepted: 08/16/2023] [Indexed: 08/26/2023] Open
Abstract
With the development and progress of medical technology, the survival rate of premature and low-birth-weight infants has increased, as has the incidence of a variety of neonatal diseases, such as hypoxic-ischemic encephalopathy, intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, and retinopathy of prematurity. These diseases cause severe health conditions with poor prognoses, and existing control methods are ineffective for such diseases. Stem cells are a special type of cells with self-renewal and differentiation potential, and their mechanisms mainly include anti-inflammatory and anti-apoptotic properties, reducing oxidative stress, and boosting regeneration. Their paracrine effects can affect the microenvironment in which they survive, thereby affecting the biological characteristics of other cells. Due to their unique abilities, stem cells have been used in treating various diseases. Therefore, stem cell therapy may open up the possibility of treating such neonatal diseases. This review summarizes the research progress on stem cells and exosomes derived from stem cells in neonatal refractory diseases to provide new insights for most researchers and clinicians regarding future treatments. In addition, the current challenges and perspectives in stem cell therapy are discussed.
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Affiliation(s)
- Fangjun Huang
- Department of Neonatology, West China Second Hospital, Sichuan University, Chengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China
| | - Yang He
- Department of Neonatology, West China Second Hospital, Sichuan University, Chengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China
| | - Meng Zhang
- Department of Neonatology, West China Second Hospital, Sichuan University, Chengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China
| | - Keren Luo
- Department of Neonatology, West China Second Hospital, Sichuan University, Chengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China
| | - Jiawen Li
- Department of Neonatology, West China Second Hospital, Sichuan University, Chengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China
| | - Jiali Li
- Department of Neonatology, West China Second Hospital, Sichuan University, Chengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China
| | - Xinyu Zhang
- Department of Neonatology, West China Second Hospital, Sichuan University, Chengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China
| | - Xiaoyan Dong
- Department of Neonatology, West China Second Hospital, Sichuan University, Chengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China
| | - Jun Tang
- Department of Neonatology, West China Second Hospital, Sichuan University, Chengdu 610041, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China
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9
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Future regenerative medicine developments and their therapeutic applications. Biomed Pharmacother 2023; 158:114131. [PMID: 36538861 DOI: 10.1016/j.biopha.2022.114131] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/05/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
Although the currently available pharmacological assays can cure most pathological disorders, they have limited therapeutic value in relieving certain disorders like myocardial infarct, peripheral vascular disease, amputated limbs, or organ failure (e.g. renal failure). Pilot studies to overcome such problems using regenerative medicine (RM) delivered promising data. Comprehensive investigations of RM in zebrafish or reptilians are necessary for better understanding. However, the precise mechanisms remain poorly understood despite the tremendous amount of data obtained using the zebrafish model investigating the exact mechanisms behind their regenerative capability. Indeed, understanding such mechanisms and their application to humans can save millions of lives from dying due to potentially life-threatening events. Recent studies have launched a revolution in replacing damaged human organs via different approaches in the last few decades. The newly established branch of medicine (known as Regenerative Medicine aims to enhance natural repair mechanisms. This can be done through the application of several advanced broad-spectrum technologies such as organ transplantation, tissue engineering, and application of Scaffolds technology (support vascularization using an extracellular matrix), stem cell therapy, miRNA treatment, development of 3D mini-organs (organoids), and the construction of artificial tissues using nanomedicine and 3D bio-printers. Moreover, in the next few decades, revolutionary approaches in regenerative medicine will be applied based on artificial intelligence and wireless data exchange, soft intelligence biomaterials, nanorobotics, and even living robotics capable of self-repair. The present work presents a comprehensive overview that summarizes the new and future advances in the field of RM.
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Clinical Efficacy of Subhypothermia in the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy Combined with Myocardial Damage. ADSORPT SCI TECHNOL 2022. [DOI: 10.1155/2022/2465490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Objective. To investigate the efficacy of subhypothermia in the treatment of neonatal hypoxic-ischemic encephalopathy (HIE) combined with myocardial damage. Methods. 136 children with HIE and myocardial damage admitted to our hospital from October 2019 to October 2021 were included in the study and were divided into study group and control group of 68 cases each according to the random number table method. The control group was given conventional treatment, and the study group was treated with subhypothermia therapy on top of the control group. Comparing the effects of treatment between the two groups. The serum levels of S-100β protein, Tau protein, neuron-specific enolase (NSE), creatine kinase (CK), creatine kinase isoenzyme MB (CK-MB), lactate dehydrogenase (LDH), alpha-hydroxybutyrate dehydrogenase (ɑ-HBDH), myoglobin (Myo), cardiac trophic factor-1 (CT-1), cardiac troponin I (cTnI), superoxide dismutase (SOD), reactive oxygen species (ROS), glutathione peroxidase (GSH-Px), interleukin-1β (IL-1β), interleukin-8 (IL-8), and tumor necrosis factor-ɑ (TNF-ɑ) were measured in both groups before and after treatment, respectively. Results. The total effective rate was higher in the study group (88.24%) than in the control group (72.06%) (
). After treatment, the serum levels of S-100β protein, Tau protein, NSE, CK, CK-MB, LDH, ɑ-HBDH, Myo, CT-1, cTnI, ROS, IL-1β, IL-8, and TNF-ɑ were reduced in both groups, and the study group was lower than the control group (
). The serum levels of SOD and GSH-Px were higher in both groups after treatment than before treatment and were higher in the study group than in the control group (
). Conclusion. Subhypothermia treatment of children with HIE combined with myocardial injury can further improve the hypoxic-ischemic state; reduce myocardial damage, oxidative stress, and inflammatory response; and has a good overall efficacy.
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Xiong Q, Li X, Xia L, Yao Z, Shi X, Dong Z. Dihydroartemisinin attenuates hypoxic-ischemic brain damage in neonatal rats by inhibiting oxidative stress. Mol Brain 2022; 15:36. [PMID: 35484595 PMCID: PMC9052669 DOI: 10.1186/s13041-022-00921-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 04/13/2022] [Indexed: 02/08/2023] Open
Abstract
Neonatal hypoxic-ischemic encephalopathy (HIE) induced by perinatal asphyxia is a major cause of neurological disability among infants. Dihydroartemisinin (DHA), derived from artemisinin, well known as an anti-malarial medicine, was proved to be able to inhibit oxidative stress and inflammation. However, whether those functions of DHA play roles in hypoxic-ischemic brain damage (HIBD), an animal model of HIE in patient which also been observed to have oxidative stress and inflammation, is unknown. In this study, we demonstrated that the DHA treatment on newborn rats significantly relieved the neuron loss and motor and cognitive impairment caused by HIBD. One of the underlying mechanisms is that DHA enhanced the anti-oxidant capacity of HIBD rats by up-regulating the total antioxidant capacity (T-AOC), gluathione reductase (GR) and catalase (CAT) while down regulating the pro-oxidative substances including hydrogen peroxide (H2O2), total nitric oxide synthase (T-NOS) and inducible nitric oxide synthase (iNOS). Thus, our study illustrated that DHA could alleviate the damage of brains and improve the cognitive and motor function of HIBD rats by inhibiting oxidative stress, provided an opportunity to interrogate potential therapeutics for affected HIE patients.
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Affiliation(s)
- Qian Xiong
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Xiaohuan Li
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Lei Xia
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Zhengyu Yao
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China
| | - Xiuyu Shi
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
| | - Zhifang Dong
- Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
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12
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Gong XB, Feng RH, Dong HM, Liu WH, Gu YN, Jiang XY, Lou YH, Xu J, Dou QL. Efficacy and Prognosis of Hyperbaric Oxygen as Adjuvant Therapy for Neonatal Hypoxic-Ischemic Encephalopathy: A Meta-Analysis Study. Front Pediatr 2022; 10:707136. [PMID: 35529335 PMCID: PMC9069061 DOI: 10.3389/fped.2022.707136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 03/09/2022] [Indexed: 01/03/2023] Open
Abstract
Background Preclinical and clinical evidence suggests that hyperbaric oxygen therapy (HBOT) may benefit newborns. The effectiveness of HBOT for neonatal hypoxic-ischemic encephalopathy (HIE) remains controversial. We conducted a meta-analysis to evaluate the efficacy and prognosis of HBOT in neonates with HIE. Methods A systematic search of eight databases was performed for available articles published between January 1, 2015, and September 30, 2020, to identify randomized controlled clinical trials (RCTs) on HBOT for neonatal HIE. Methodological quality assessment was performed by applying the simple procedure detailed by the Cochrane collaboration. Afterward, quality assessment and data analysis were performed using Revman 5.3 software. STATA 15 software was used to detect publication bias as well as for sensitivity analysis. Results A total of 46 clinical RCTs were selected for the study and included 4,199 patients with neonatal HIE. The results indicated that HBOT significantly improved the total efficiency (TEF) of treatment for neonatal HIE patients [odds ratio (OR) = 4.61, 95% confidence interval (CI) (3.70, 5.75), P < 0.00001] and reduced the risk of sequelae (OR = 0.23, 95% CI (0.16, 0.33), P < 0.00001) and the neonatal behavioral neurological assessment (NBNA) scores [mean difference (MD) = 4.51, 95%CI (3.83,5.19, P < 0.00001)]. Conclusion In light of the effectiveness of HBOT neonatal HIE, this meta-analysis suggested that HBOT can be a potential therapy for the treatment of neonatal HIE. Due to the heterogeneity of studies protocol and patient selection being only from China, more research is needed before this therapy can be widely implemented in the clinic. Protocol Registration PROSPERO (ID: CRD42020210639). Available online at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020210639.
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Affiliation(s)
- Xiu-Bing Gong
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Rui-Hua Feng
- Department of Health Economics, Institute of Medical Information, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong-Mei Dong
- No. 941 Hospital of the Joint Support Force of People’s Liberation Army (PLA), Xining, China
| | - Wen-Hua Liu
- Shenzhen Bao’an People’s Hospital, Shenzhen, China
| | - Ya-Nan Gu
- Shenzhen Bao’an People’s Hospital, Shenzhen, China
| | - Xiang-Yue Jiang
- Emergency Department, The Second Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Ye-Hao Lou
- The First School of Clinical Medicine, Guangdong Medical University, Zhanjiang, China
| | - Jun Xu
- State Key Laboratory of Complex Severe and Rare Diseases, Emergency Department, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qing-Li Dou
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Shenzhen Bao’an People’s Hospital, Shenzhen, China
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13
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Lyu H, Sun DM, Ng CP, Cheng WS, Chen JF, He YZ, Lam SY, Zheng ZY, Huang GD, Wang CC, Young W, Poon WS. Umbilical Cord Blood Mononuclear Cell Treatment for Neonatal Rats With Hypoxic Ischemia. Front Cell Neurosci 2022; 16:823320. [PMID: 35308119 PMCID: PMC8924590 DOI: 10.3389/fncel.2022.823320] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 01/13/2022] [Indexed: 12/12/2022] Open
Abstract
Background Hypoxic-ischemic encephalopathy (HIE) occurs when an infant’s brain has not received adequate oxygen and blood supply, resulting in ischemic and hypoxic damage. Currently, supportive care and hypothermia therapy have been the standard treatment for HIE. However, there are still over 20% of treated infants died and 19–30% survived with significant disability. HIE animal model was first established by Rice et al., involving the ligation of one common carotid artery followed by hypoxia. In this study, we investigated human umbilical cord blood (HUCB) and its two components mononuclear cell (MNC) and red cell fraction (RCF) in both short and long term study using a modified HIE rat model. Methods In this modified HIE model, both common carotid arteries were occluded, breathing 8% oxygen in a hypoxic chamber for 60-min, followed by the release of the common carotid arteries ligature, mimicking reperfusion injury. For cell therapeutic study, cells were intravenously injected to HIE rat pups, and both behavioral and histological changes were assessed at selected time points. Result Statistically significant behavioral improvements were demonstrated on Day 7 and 1 month between saline treated HIE rats and UCB/MNC treated rats. However, at 3 months, the therapeutic improvements were only showed between saline treated HIE animals and MNC treated HIE rats. For histological analysis 1 month after cell injection, the number of functional neurons were statistically increased between saline treated HIE and UCB/MNC/RCF treated HIE rats. At 3 months, the significant increase in functional neurons was only present in MNC treated HIE rats. Conclusion We have used a bilateral temporary occlusion of 60 min, a moderately brain damaged model, for cell therapeutic studies. HUCB mononuclear cell (MNC) therapy showed benefits in neonatal HIE rats in both short and long term behavioral and histological assessments.
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Affiliation(s)
- Hao Lyu
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
- Shenzhen Key Laboratory of Neurosurgery, Department of Neurosurgery, The Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Dong Ming Sun
- W. M. Keck Center for Collaborative Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, United States
| | - Chi Ping Ng
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Wendy S. Cheng
- Mononuclear Therapeutics Limited, Hong Kong, Hong Kong SAR, China
| | - Jun Fan Chen
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Yu Zhong He
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Sin Yu Lam
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Zhi Yuan Zheng
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
- Department of Neurosurgery, Hainan Hospital of People’s Liberation Army General Hospital, Sanya, China
| | - Guo Dong Huang
- Shenzhen Key Laboratory of Neurosurgery, Department of Neurosurgery, The Shenzhen Second People’s Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Chi Chiu Wang
- Department of Obstetrics and Gynecology, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, Chinese University of Hong Kong-Sichuan University Joint Laboratory in Reproductive Medicine, Shatin, Hong Kong SAR, China
| | - Wise Young
- W. M. Keck Center for Collaborative Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ, United States
- *Correspondence: Wise Young,
| | - Wai Sang Poon
- Division of Neurosurgery, Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
- *Correspondence: Wise Young,
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14
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Chand K, Nano R, Wixey J, Patel J. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:372-382. [PMID: 35485440 PMCID: PMC9052430 DOI: 10.1093/stcltm/szac005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 12/12/2021] [Indexed: 11/25/2022] Open
Abstract
Fetal growth restriction (FGR) occurs when a fetus is unable to grow normally due to inadequate nutrient and oxygen supply from the placenta. Children born with FGR are at high risk of lifelong adverse neurodevelopmental outcomes, such as cerebral palsy, behavioral issues, and learning and attention difficulties. Unfortunately, there is no treatment to protect the FGR newborn from these adverse neurological outcomes. Chronic inflammation and vascular disruption are prevalent in the brains of FGR neonates and therefore targeted treatments may be key to neuroprotection. Tissue repair and regeneration via stem cell therapies have emerged as a potential clinical intervention for FGR babies at risk for neurological impairment and long-term disability. This review discusses the advancement of research into stem cell therapy for treating neurological diseases and how this may be extended for use in the FGR newborn. Leading preclinical studies using stem cell therapies in FGR animal models will be highlighted and the near-term steps that need to be taken for the development of future clinical trials.
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Affiliation(s)
- Kirat Chand
- UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia
| | - Rachel Nano
- Cancer and Ageing Research Program, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Julie Wixey
- Julie Wixey, Faculty of Medicine, Royal Brisbane and Women’s Hospital, The University of Queensland Centre for Clinical Research, Herston 4029 QLD, Australia.
| | - Jatin Patel
- Corresponding authors: Jatin Patel, Translational Research Institute, Queensland University of Technology, 37 Kent Street, Woolloongabba 4102 QLD, Australia.
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15
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Chakkarapani AA, Aly H, Benders M, Cotten CM, El-Dib M, Gressens P, Hagberg H, Sabir H, Wintermark P, Robertson NJ. Therapies for neonatal encephalopathy: Targeting the latent, secondary and tertiary phases of evolving brain injury. Semin Fetal Neonatal Med 2021; 26:101256. [PMID: 34154945 DOI: 10.1016/j.siny.2021.101256] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
In term and near-term neonates with neonatal encephalopathy, therapeutic hypothermia protocols are well established. The current focus is on how to improve outcomes further and the challenge is to find safe and complementary therapies that confer additional protection, regeneration or repair in addition to cooling. Following hypoxia-ischemia, brain injury evolves over three main phases (latent, secondary and tertiary), each with a different brain energy, perfusion, neurochemical and inflammatory milieu. While therapeutic hypothermia has targeted the latent and secondary phase, we now need therapies that cover the continuum of brain injury that spans hours, days, weeks and months after the initial event. Most agents have several therapeutic actions but can be broadly classified under a predominant action (e.g., free radical scavenging, anti-apoptotic, anti-inflammatory, neuroregeneration, and vascular effects). Promising early/secondary phase therapies include Allopurinol, Azithromycin, Exendin-4, Magnesium, Melatonin, Noble gases and Sildenafil. Tertiary phase agents include Erythropoietin, Stem cells and others. We review a selection of promising therapeutic agents on the translational pipeline and suggest a framework for neuroprotection and neurorestoration that targets the evolving injury.
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Affiliation(s)
| | - Hany Aly
- Cleveland Clinic Children's Hospital, Cleveland, OH, USA.
| | - Manon Benders
- Department of Neonatology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
| | - C Michael Cotten
- Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
| | - Mohamed El-Dib
- Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Pierre Gressens
- Université de Paris, NeuroDiderot, Inserm, Paris, France; Centre for the Developing Brain, Department of Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, SE1 7EH, United Kingdom.
| | - Henrik Hagberg
- Centre for the Developing Brain, Department of Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, SE1 7EH, United Kingdom; Centre of Perinatal Medicine & Health, Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
| | - Hemmen Sabir
- Department of Neonatology and Pediatric Intensive Care, Children's Hospital University of Bonn, Bonn, Germany; German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany.
| | - Pia Wintermark
- Department of Pediatrics, Division of Newborn Medicine, Montreal Children's Hospital, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
| | - Nicola J Robertson
- Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, Edinburgh BioQuarter, Edinburgh, United Kingdom; Institute for Women's Health, University College London, London, United Kingdom.
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16
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Rios DR, Lapointe A, Schmolzer GM, Mohammad K, VanMeurs KP, Keller RL, Sehgal A, Lakshminrusimha S, Giesinger RE. Hemodynamic optimization for neonates with neonatal encephalopathy caused by a hypoxic ischemic event: Physiological and therapeutic considerations. Semin Fetal Neonatal Med 2021; 26:101277. [PMID: 34481738 DOI: 10.1016/j.siny.2021.101277] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Neonatal encephalopathy due to a hypoxic-ischemic event is commonly associated with cardiac dysfunction and acute pulmonary hypertension; both therapeutic hypothermia and rewarming modify loading conditions and blood flow. The pathophysiological contributors to disease are complex with a high degree of clinical overlap and traditional bedside measures used to assess circulatory adequacy have multiple confounders. Comprehensive, quantitative echocardiography may be used to delineate the relative contribution of lung parenchymal, pulmonary vascular, and cardiac disease to hypotension and/or hypoxemic respiratory failure. In this review, we provide a detailed overview of the contributors to hemodynamic instability following perinatal hypoxic-ischemic injury. Our proposed approach to therapy focuses on physiopathological considerations with interventions individualized to this potentially complex condition and considers the pharmacological idiosyncrasies, which may occur among neonates with NE presenting with multiorgan dysfunction while undergoing therapeutic hypothermia.
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Affiliation(s)
- Danielle R Rios
- Department of Pediatrics, Division of Neonatology, University of Iowa, MS 200 Hawkins Drive 8800 JPP, Iowa City, IA, 52242, USA.
| | - Anie Lapointe
- CHU Ste-Justine, Montreal University, CHU Sainte-Justine 3175, chemin Côte Sainte-Catherine Montréal (Québec), H3T 1C5, Canada.
| | - Georg M Schmolzer
- Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, 10240 Kingsway Avenue NW AB, Edmonton, T5H 3V9, Canada.
| | - Khorshid Mohammad
- Department of Pediatrics, Section of Neonatology, University of Calgary, 28 Oki Drive NW, Calgary, AB, T3B 6A8, Canada.
| | - Krisa P VanMeurs
- Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children's Hospital, Center for Academic Medicine Division of Neonatology - MC 5660 453 Quarry Road, Palo Alto, CA, 94304, USA.
| | - Roberta L Keller
- Department of Pediatrics, University of California San Francisco, 550 16th. Street, San Francisco, CA, 94158, USA.
| | - Arvind Sehgal
- Department of Pediatrics, Monash University, 246 Clayton Road, Clayton, Melbourne, VIC, 3168, Australia.
| | - Satyan Lakshminrusimha
- Department of Pediatrics, Division of Neonatology, University of California, Davis, 2516 Stockton Blvd, Sacramento, CA 95817, USA.
| | - Regan E Giesinger
- Department of Pediatrics, Division of Neonatology, University of Iowa, MS 200 Hawkins Drive 8800 JPP, Iowa City, IA, 52242, USA.
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17
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Kabatas S, Civelek E, Savrunlu EC, Kaplan N, Boyalı O, Diren F, Can H, Genç A, Akkoç T, Karaöz E. Feasibility of allogeneic mesenchymal stem cells in pediatric hypoxic-ischemic encephalopathy: Phase I study. World J Stem Cells 2021; 13:470-484. [PMID: 34136076 PMCID: PMC8176840 DOI: 10.4252/wjsc.v13.i5.470] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 02/26/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of death and long-term neurological impairment in the pediatric population. Despite a limited number of treatments to cure HIE, stem cell therapies appear to be a potential treatment option for brain injury resulting from HIE.
AIM To investigate the efficacy and safety of stem cell-based therapies in pediatric patients with HIE.
METHODS The study inclusion criteria were determined as the presence of substantial deficit and disability caused by HIE. Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) were intrathecally (IT), intramuscularly (IM), and intravenously administered to participants at a dose of 1 × 106/kg for each administration route twice monthly for 2 mo. In different follow-up durations, the effect of WJ-MSCs administration on HIE, the quality of life, prognosis of patients, and side effects were investigated, and patients were evaluated for neurological, cognitive functions, and spasticity using the Wee Functional Independence Measure (Wee FIM) Scale and Modified Ashworth (MA) Scale.
RESULTS For all participants (n = 6), the mean duration of exposure to hypoxia was 39.17 + 18.82 min, the mean time interval after HIE was 21.83 ± 26.60 mo, the mean baseline Wee FIM scale score was 13.5 ± 0.55, and the mean baseline MA scale score was 35 ± 9.08. Three patients developed only early complications such as low-grade fever, mild headache associated with IT injection, and muscle pain associated with IM injection, all of which were transient and disappeared within 24 h. The treatment was evaluated to be safe and effective as demonstrated by magnetic resonance imaging examinations, electroencephalographies, laboratory tests, and neurological and functional scores of patients. Patients exhibited significant improvements in all neurological functions through a 12-mo follow-up. The mean Wee FIM scale score of participants increased from 13.5 ± 0.55 to 15.17 ± 1.6 points (mean ± SD) at 1 mo (z = - 1.826, P = 0.068) and to 23.5 ± 3.39 points at 12 mo (z = -2.207, P = 0.027) post-treatment. The percentage of patients who achieved an excellent functional improvement (Wee FIM scale total score = 126) increased from 10.71% (at baseline) to 12.03% at 1 mo and to 18.65% at 12 mo post-treatment.
CONCLUSION Both the triple-route and multiple WJ-MSC implantations were safe and effective in pediatric patients with HIE with significant neurological and functional improvements. The results of this study support conducting further randomized, placebo-controlled studies on this treatment in the pediatric population.
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Affiliation(s)
- Serdar Kabatas
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, Istanbul 34255, Turkey
- Pediatric Allergy-Immunology, Marmara University, Institute of Health Sciences, Istanbul 34854, Turkey
- Center for Stem Cell & Gene Therapy Research and Practice, University of Health Sciences, Istanbul 34255, Turkey
| | - Erdinç Civelek
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, Istanbul 34255, Turkey
- Pediatric Allergy-Immunology, Marmara University, Institute of Health Sciences, Istanbul 34854, Turkey
| | - Eyüp Can Savrunlu
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, Istanbul 34255, Turkey
| | - Necati Kaplan
- Department of Neurosurgery, Istanbul Rumeli University, Çorlu Reyap Hospital, Tekirdağ 59860, Turkey
| | - Osman Boyalı
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, Istanbul 34255, Turkey
| | - Furkan Diren
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, Istanbul 34255, Turkey
| | - Halil Can
- Department of Neurosurgery, Istanbul Biruni University, Faculty of Medicine, Istanbul 34010, Turkey
- Department of Neurosurgery, Istanbul Medicine Hospital, Istanbul 34203, Turkey
| | - Ali Genç
- Department of Neurosurgery, Istanbul Asya Hospital, Istanbul 34250, Turkey
| | - Tunç Akkoç
- Pediatric Allergy-Immunology, Marmara University, Istanbul 34899, Turkey
| | - Erdal Karaöz
- Center for Regenerative Medicine and Stem Cell Research & Manufacturing (LivMedCell), Liv Hospital, Istanbul 34340, Turkey
- Department of Histology and Embryology, Istinye University, Faculty of Medicine, Istanbul 34010, Turkey
- Center for Stem Cell and Tissue Engineering Research and Practice, Istinye University, Istanbul 34340, Turkey
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Nabetani M, Mukai T, Shintaku H. Preventing Brain Damage from Hypoxic-Ischemic Encephalopathy in Neonates: Update on Mesenchymal Stromal Cells and Umbilical Cord Blood Cells. Am J Perinatol 2021; 39:1754-1763. [PMID: 33853147 PMCID: PMC9674406 DOI: 10.1055/s-0041-1726451] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
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..
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Affiliation(s)
- Makoto Nabetani
- Department of Pediatrics, Yodogawa Christian Hospital, Osaka, Japan,Address for correspondence Makoto Nabetani, MD, PhD Department of Pediatrics, Yodogawa Christian HospitalOsaka, Japan, 1-7-50 Kunijima, Higashi-yodogawa-ku, Osaka 5330024Japan
| | - Takeo Mukai
- Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Haruo Shintaku
- Department of Pediatrics, Faculty of Medicine, Osaka City University, Osaka, Japan
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Kabataş S, Civelek E, Kaplan N, Savrunlu EC, Sezen GB, Chasan M, Can H, Genç A, Akyuva Y, Boyalı O, Diren F, Karaoz E. Phase I study on the safety and preliminary efficacy of allogeneic mesenchymal stem cells in hypoxic-ischemic encephalopathy. World J Exp Med 2021; 11:17-29. [PMID: 33821203 PMCID: PMC8010270 DOI: 10.5493/wjem.v11.i2.17] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 02/19/2021] [Accepted: 03/12/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hypoxic-ischemic encephalopathy (HIE) is a leading cause of morbidity and mortality in the adult as well as in the neonate, with limited options for treatment and significant dysfunctionality.
AIM To investigate the safety and preliminary efficacy of allogeneic mesenchymal stem cells (MSCs) in HIE patients.
METHODS Patients who had HIE for at least 6 mo along with significant dysfunction and disability were included. All patients were given Wharton’s jelly-derived MSCs at 1 × 106/kg intrathecally, intravenously, and intramuscularly twice a month for two months. The therapeutic effects and prognostic implications of MSCs were evaluated by multiple follow-ups. Functional independence measure (FIM), modified Ashworth, and Karnofsky scales were used to assess any side effects, neurological and cognitive functions, and overall outcomes.
RESULTS The 8 subjects included in the study had a mean age of 33.25 ± 10.18 years. Mean HIE exposure and mean post-HIE durations were 45.63 ± 10.18 and 19.67 ± 29.04 mo, respectively. Mean FIM score was 18.38 ± 1.06, mean modified Ashworth score was 43.5 ± 4.63, and mean Karnofsky score was 20. For the first 24 h, 5 of the patients experienced a subfebrile state, accompanied by mild headaches due to intrathecally administration and muscle pain because of intramuscularly administration. Neurological and functional examinations, laboratory tests, electroencephalography, and magnetic resonance imaging were performed to assess safety of treatment. Mean FIM score increased by 20.88 ± 3.31 in the first month (P = 0.027) and by 31.38 ± 14.69 in 12 mo (P = 0.012). The rate of patients with an FIM score of 126 increased from 14.58% to 16.57% in the first month and 24.90% in 12 mo.
CONCLUSION Multiple triple-route Wharton’s jelly-derived MSC administrations were found to be safe for HIE patients, indicating neurological and functional improvement. Based on the findings obtained here, further randomized and placebo research could be performed.
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Affiliation(s)
- Serdar Kabataş
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, İstanbul 34255, Turkey
- Pediatric Allergy-Immunology, Marmara University, Institute of Health Sciences, İstanbul 34854, Turkey
- Center for Stem Cell and Gene Therapy Research and Practice, University of Health Sciences, İstanbul 34255, Turkey
| | - Erdinç Civelek
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, İstanbul 34255, Turkey
- Pediatric Allergy-Immunology, Marmara University, Institute of Health Sciences, İstanbul 34854, Turkey
| | - Necati Kaplan
- Department of Neurosurgery, Istanbul Rumeli University, Çorlu Reyap Hospital, Tekirdağ 59860, Turkey
| | - Eyüp Can Savrunlu
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, İstanbul 34255, Turkey
| | - Gülseli Berivan Sezen
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, İstanbul 34255, Turkey
| | - Mourat Chasan
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, İstanbul 34255, Turkey
| | - Halil Can
- Department of Neurosurgery, İstanbul Biruni University, Faculty of Medicine, İstanbul 34010, Turkey
- Department of Neurosurgery, İstanbul Medicine Hospital, İstanbul 34203, Turkey
| | - Ali Genç
- Department of Neurosurgery, İstanbul Asya Hospital, İstanbul 34250, Turkey
| | - Yener Akyuva
- Department of Neurosurgery, Mustafa Kemal University, Faculty of Medicine, Hatay 31060, Turkey
| | - Osman Boyalı
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, İstanbul 34255, Turkey
| | - Furkan Diren
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, İstanbul 34255, Turkey
| | - Erdal Karaoz
- Center for Regenerative Medicine and Stem Cell Research and Manufacturing (LivMedCell), Liv Hospital, İstanbul 34340, Turkey
- Department of Histology and Embryology, İstinye University, Faculty of Medicine, İstanbul 34010, Turkey
- Center for Stem Cell and Tissue Engineering Research and Practice, İstinye University, İstanbul 34340, Turkey
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20
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Stem Cell Therapy for Neonatal Hypoxic-Ischemic Encephalopathy: A Systematic Review of Preclinical Studies. Int J Mol Sci 2021; 22:ijms22063142. [PMID: 33808671 PMCID: PMC8003344 DOI: 10.3390/ijms22063142] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/12/2021] [Accepted: 03/17/2021] [Indexed: 12/15/2022] Open
Abstract
Neonatal hypoxic-ischemic encephalopathy (HIE) is an important cause of mortality and morbidity in the perinatal period. This condition results from a period of ischemia and hypoxia to the brain of neonates, leading to several disorders that profoundly affect the daily life of patients and their families. Currently, therapeutic hypothermia (TH) is the standard of care in developing countries; however, TH is not always effective, especially in severe cases of HIE. Addressing this concern, several preclinical studies assessed the potential of stem cell therapy (SCT) for HIE. With this systematic review, we gathered information included in 58 preclinical studies from the last decade, focusing on the ones using stem cells isolated from the umbilical cord blood, umbilical cord tissue, placenta, and bone marrow. Outstandingly, about 80% of these studies reported a significant improvement of cognitive and/or sensorimotor function, as well as decreased brain damage. These results show the potential of SCT for HIE and the possibility of this therapy, in combination with TH, becoming the next therapeutic approach for HIE. Nonetheless, few preclinical studies assessed the combination of TH and SCT for HIE, and the existent studies show some contradictory results, revealing the need to further explore this line of research.
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21
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Wei M, Li S, Yang Z, Cheng C, Li T, Le W. Tetrahedral DNA nanostructures functionalized by multivalent microRNA132 antisense oligonucleotides promote the differentiation of mouse embryonic stem cells into dopaminergic neurons. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2021; 34:102375. [PMID: 33617970 DOI: 10.1016/j.nano.2021.102375] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 02/04/2021] [Accepted: 02/08/2021] [Indexed: 11/29/2022]
Abstract
MicroRNA132 (miR132) negatively regulates the differentiation of mouse embryonic stem cells (ESCs) into dopaminergic (DAergic) neurons; in contrast, antisense oligonucleotide against miR132 (miR132-ASO) effectively blocks the activity of endogenous miR132 and thereafter promotes the differentiation of DAergic neurons. However, it is difficult for miR132-ASO to enter cells without a suitable delivery system. Tetrahedral DNA nanostructures (TDNs), as a new type of DNA-based nanocarrier, have great potential in biomedical applications and even have been reported to promote stem cell differentiation. In this study, we developed functional multivalent DNA nanostructures by appending miR132-ASO motifs to three-dimensional TDNs (miR132-ASO-TDNs). Our data clearly revealed that miR132-ASO-TDNs exposure can promote the differentiation of ESCs into DAergic neurons as well as elevate DA release from differentiated DAergic neurons. MiR132-ASO-TDNs could serve as a novel biofunctional nanomaterial to improve the efficiency of DAergic neurons differentiation. Our findings may also provide a new approach for stem cell therapy against neurodegenerative diseases.
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Affiliation(s)
- Min Wei
- Liaoning Provincial Center for Clinical Research on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China; Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China
| | - Song Li
- Liaoning Provincial Center for Clinical Research on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China; Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China
| | - Zhaofei Yang
- Liaoning Provincial Center for Clinical Research on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China; Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China
| | - Cheng Cheng
- Liaoning Provincial Center for Clinical Research on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China; Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China
| | - Tianbai Li
- Liaoning Provincial Center for Clinical Research on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China; Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China
| | - Weidong Le
- Liaoning Provincial Center for Clinical Research on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China; Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China.
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22
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Shintaku H. Prevention and treatment of cerebral palsy with cord blood stem cells and cord-derived mesenchymal stem cells. Neural Regen Res 2021; 16:672-673. [PMID: 33063719 PMCID: PMC8067942 DOI: 10.4103/1673-5374.293139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Affiliation(s)
- Haruo Shintaku
- Donated Course "Disability medicine and Regenerative medicine", Osaka City University Graduate School of Medicine, Osaka, Japan
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23
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da Silva TFG, de Bem GF, da Costa CA, Santos IB, Soares RDA, Ognibene DT, Rito-Costa F, Cavalheira MA, da Conceição SP, Ferraz MR, Resende AC. Prenatal hypoxia predisposes vascular functional and structural changes associated with oxidative stress damage and depressive behavior in adult offspring male rats. Physiol Behav 2020; 230:113293. [PMID: 33338483 DOI: 10.1016/j.physbeh.2020.113293] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 12/11/2020] [Accepted: 12/12/2020] [Indexed: 01/05/2023]
Abstract
Intrauterine hypoxia-ischemia (HI) provides a strong stimulus for a developmental origin of both the central nervous system and cardiovascular diseases. This study aimed to investigate vascular functional and structural changes, oxidative stress damage, and behavioral alterations in adult male offspring submitted to HI during pregnancy. The pregnant Wistar rats had a uterine artery clamped for 45 min on the 18th gestational day, submitting the offspring to hypoxic-ischemic conditions. The Sham group passed to the same surgical procedure as the HI rats, without occlusion of the maternal uterine artery, and the controls consisted of non-manipulated healthy animals. After weaning, the male pups were divided into three groups: control, sham, and HI, according to the maternal procedure. At postnatal day 90 (P90), the adult male offspring performed the open field and forced swim tests. In P119, the rats had their blood pressure checked and were euthanized. Prenatal HI induced a depressive behavior in adult male offspring associated with a reduced vasodilator response to acetylcholine in perfused mesenteric arterial bed, and reduced superoxide dismutase and glutathione peroxidase activities in the aorta compared to control and sham groups. Prenatal HI also increased the vasoconstrictor response to norepinephrine, the media thickness, collagen deposition, and the oxidative damage in the aorta from adult male offspring compared to control and sham groups. Our results suggest an association among prenatal HI and adult vascular structural and functional changes, oxidative stress damage, and depressive behavior.
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Affiliation(s)
| | - Graziele Freitas de Bem
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Cristiane Aguiar da Costa
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Izabelle Barcellos Santos
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Ricardo de Andrade Soares
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Dayane Teixeira Ognibene
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Fernanda Rito-Costa
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Mariana Alencar Cavalheira
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | | | - Marcos Rochedo Ferraz
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Angela Castro Resende
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil.
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24
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Bruschettini M, Romantsik O, Moreira A, Ley D, Thébaud B. Stem cell-based interventions for the prevention of morbidity and mortality following hypoxic-ischaemic encephalopathy in newborn infants. Cochrane Database Syst Rev 2020; 8:CD013202. [PMID: 32813884 PMCID: PMC7438027 DOI: 10.1002/14651858.cd013202.pub2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hypoxic-ischaemic encephalopathy (HIE) is a leading cause of mortality and long-term neurological sequelae, affecting thousands of children worldwide. Current therapies to treat HIE are limited to cooling. Stem cell-based therapies offer a potential therapeutic approach to repair or regenerate injured brain tissue. These preclinical findings have now culminated in ongoing human neonatal trials. OBJECTIVES To determine the efficacy and safety of stem cell-based interventions for the treatment of hypoxic-ischaemic encephalopathy (HIE) in newborn infants. SEARCH METHODS We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 5), MEDLINE via PubMed (1966 to 8 June 2020), Embase (1980 to 8 June 2020), and CINAHL (1982 to 8 June 2020). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA Randomised controlled trials, quasi-randomised controlled trials and cluster trials comparing 1) stem cell-based interventions (any type) compared to control (placebo or no treatment); 2) use of mesenchymal stem/stromal cells (MSCs) of type (e.g. number of doses or passages) or source (e.g. autologous versus allogeneic, or bone marrow versus cord) versus MSCs of other type or source; 3) use of stem cell-based interventions other than MSCs of type (e.g. mononuclear cells, oligodendrocyte progenitor cells, neural stem cells, hematopoietic stem cells, and inducible pluripotent stem cells) or source (e.g. autologous versus allogeneic, or bone marrow versus cord) versus stem cell-based interventions other than MSCs of other type or source; or 4) MSCs versus stem cell-based interventions other than MSCs. DATA COLLECTION AND ANALYSIS For each of the included trials, two authors independently planned to extract data (e.g. number of participants, birth weight, gestational age, type and source of MSCs or other stem cell-based interventions) and assess the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow-up). The primary outcomes considered in this review are all-cause neonatal mortality, major neurodevelopmental disability, death or major neurodevelopmental disability assessed at 18 to 24 months of age. We planned to use the GRADE approach to assess the quality of evidence. MAIN RESULTS Our search strategy yielded 616 references. Two review authors independently assessed all references for inclusion. We did not find any completed studies for inclusion. Fifteen RCTs are currently registered and ongoing. We describe the three studies we excluded. AUTHORS' CONCLUSIONS There is currently no evidence from randomised trials that assesses the benefit or harms of stem cell-based interventions for the prevention of morbidity and mortality following hypoxic-ischaemic encephalopathy in newborn infants.
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Affiliation(s)
- Matteo Bruschettini
- Department of Clinical Sciences Lund, Paediatrics, Lund University, Skåne University Hospital, Lund, Sweden
- Cochrane Sweden, Lund University, Skåne University Hospital, Lund, Sweden
| | - Olga Romantsik
- Department of Clinical Sciences Lund, Paediatrics, Lund University, Skåne University Hospital, Lund, Sweden
| | - Alvaro Moreira
- Pediatrics, Division of Neonatology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - David Ley
- Department of Clinical Sciences Lund, Paediatrics, Lund University, Skåne University Hospital, Lund, Sweden
| | - Bernard Thébaud
- Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Canada
- Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research, Ottawa, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada
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25
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Sowmithra S, Jain NK, Datta I. Evaluating In Vitro Neonatal Hypoxic-Ischemic Injury Using Neural Progenitors Derived from Human Embryonic Stem Cells. Stem Cells Dev 2020; 29:929-951. [DOI: 10.1089/scd.2020.0018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Affiliation(s)
- Sowmithra Sowmithra
- Department of Biophysics, National Institute of Mental Health and Neurosciences, Institute of National Importance, Bengaluru, India
| | - Nishtha Kusum Jain
- Department of Biophysics, National Institute of Mental Health and Neurosciences, Institute of National Importance, Bengaluru, India
| | - Indrani Datta
- Department of Biophysics, National Institute of Mental Health and Neurosciences, Institute of National Importance, Bengaluru, India
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26
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DISDIER C, STONESTREET BS. Hypoxic-ischemic-related cerebrovascular changes and potential therapeutic strategies in the neonatal brain. J Neurosci Res 2020; 98:1468-1484. [PMID: 32060970 PMCID: PMC7242133 DOI: 10.1002/jnr.24590] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 01/20/2020] [Accepted: 01/28/2020] [Indexed: 12/11/2022]
Abstract
Perinatal hypoxic-ischemic (HI)-related brain injury is an important cause of morbidity and long-standing disability in newborns. The only currently approved therapeutic strategy available to reduce brain injury in the newborn is hypothermia. Therapeutic hypothermia can only be used to treat HI encephalopathy in full-term infants and survivors remain at high risk for a wide spectrum of neurodevelopmental abnormalities as a result of residual brain injury. Therefore, there is an urgent need for adjunctive therapeutic strategies. Inflammation and neurovascular damage are important factors that contribute to the pathophysiology of HI-related brain injury and represent exciting potential targets for therapeutic intervention. In this review, we address the role of each component of the neurovascular unit (NVU) in the pathophysiology of HI-related injury in the neonatal brain. Disruption of the blood-brain barrier (BBB) observed in the early hours after an HI-related event is associated with a response at the basal lamina level, which comprises astrocytes, pericytes, and immune cells, all of which could affect BBB function to further exacerbate parenchymal injury. Future research is required to determine potential drugs that could prevent or attenuate neurovascular damage and/or augment repair. However, some studies have reported beneficial effects of hypothermia, erythropoietin, stem cell therapy, anti-cytokine therapy and metformin in ameliorating several different facets of damage to the NVU after HI-related brain injury in the perinatal period.
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Affiliation(s)
- Clémence DISDIER
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, USA
| | - Barbara S STONESTREET
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, USA
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27
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Volpe JJ. Commentary - Exosomes: Realization of the great therapeutic potential of stem cells. J Neonatal Perinatal Med 2020; 13:287-291. [PMID: 32444568 PMCID: PMC7592649 DOI: 10.3233/npm-200477] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- J J Volpe
- Department of Neurology, Harvard Medical School, Boston, MA, USA.,Department of Pediatric Newborn Medicine, Harvard Medical School, Boston, MA, USA
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28
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Liu JY, Wang KX, Huang LY, Wan B, Zhao GY, Zhao FY. [Expression and role of Pim1 in cultured cortical neurons with oxygen-glucose deprivation/reoxygen injury]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2020; 22:512-518. [PMID: 32434650 PMCID: PMC7389388 DOI: 10.7499/j.issn.1008-8830.1911045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 04/23/2020] [Indexed: 06/11/2023]
Abstract
OBJECTIVE To study the expression and effect of Pim1 in primary cortical neurons after hypoxic-ischemic injury. METHODS Cortical neurons were isolated from 1-day-old C57BL/6 mice and cultured in neurobasal medium. On the 8th day of neuron culture, cells were subjected to oxygen-glucose deprivation/reoxygen (OGD/R) treatment to mimic in vivo hypoxic injury of neurons. Briefly, medium were changed to DMEM medium, and cells were cultured in 1% O2 for 3 hours and then changed back to normal medium and conditions. Cells were collected at 0 hour, 6 hours, 12 hours and 24 hours after OGD/R. Primary neurons were transfected with Pim1 overexpression plasmid or mock plasmid, and then were exposed to normal conditions or OGD/R treatment. They were named as Pim1 group, control group, OGD/R group and OGD/R+Pim1 group respectively. Real-time PCR was used to detect Pim1 mRNA expression. Western blot was used to detect the protein expression of Pim1 and apoptotic related protein cleaved caspase 3 (CC3). TUNEL staining was used to detect cell apoptosis. RESULTS Real-time PCR and Western blot results showed that Pim1 mRNA and protein were significantly decreased in neurons after OGD/R. They began to decrease at 0 hour after OGD/R, reached to the lowest at 12 hours after OGD/R, and remained at a lower level at 24 hours after OGD/R (P<0.01). Overexpression of Pim1 significantly upregulated the protein level of Pim1. Under OGD/R conditions, the CC3 expression and the apoptosis rate in cells of the Pim1 group were significantly lower than in un-transfected cells (P<0.01). CONCLUSIONS Hypoxic-ischemic injury may decrease Pim1 expression in neurons. Overexpressed Pim1 may inhibit apoptosis induced by OGD/R.
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Affiliation(s)
- Jun-Yan Liu
- Department of Neonatology, Binzhou Medical University Hospital, Binzhou, Shandong 256600, China.
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Exploring Perinatal Asphyxia by Metabolomics. Metabolites 2020; 10:metabo10040141. [PMID: 32260446 PMCID: PMC7240960 DOI: 10.3390/metabo10040141] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/25/2020] [Accepted: 04/02/2020] [Indexed: 02/06/2023] Open
Abstract
Brain damage related to perinatal asphyxia is the second cause of neuro-disability worldwide. Its incidence was estimated in 2010 as 8.5 cases per 1000 live births worldwide, with no further recent improvement even in more industrialized countries. If so, hypoxic-ischemic encephalopathy is still an issue of global health concern. It is thought that a consistent number of cases may be avoided, and its sequelae may be preventable by a prompt and efficient physical and therapeutic treatment. The lack of early, reliable, and specific biomarkers has up to now hampered a more effective use of hypothermia, which represents the only validated therapy for this condition. The urge to unravel the biological modifications underlying perinatal asphyxia and hypoxic-ischemic encephalopathy needs new diagnostic and therapeutic tools. Metabolomics for its own features is a powerful approach that may help for the identification of specific metabolic profiles related to the pathological mechanism and foreseeable outcome. The metabolomic profiles of animal and human infants exposed to perinatal asphyxia or developing hypoxic-ischemic encephalopathy have so far been investigated by means of 1H nuclear magnetic resonance spectroscopy and mass spectrometry coupled with gas or liquid chromatography, leading to the identification of promising metabolomic signatures. In this work, an extensive review of the relevant literature was performed.
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30
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Tsuji M, Sawada M, Watabe S, Sano H, Kanai M, Tanaka E, Ohnishi S, Sato Y, Sobajima H, Hamazaki T, Mori R, Oka A, Ichiba H, Hayakawa M, Kusuda S, Tamura M, Nabetani M, Shintaku H. Autologous cord blood cell therapy for neonatal hypoxic-ischaemic encephalopathy: a pilot study for feasibility and safety. Sci Rep 2020; 10:4603. [PMID: 32165664 PMCID: PMC7067794 DOI: 10.1038/s41598-020-61311-9] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 02/03/2020] [Indexed: 02/02/2023] Open
Abstract
Neonatal hypoxic-ischaemic encephalopathy (HIE) is a serious condition; many survivors develop neurological impairments, including cerebral palsy and intellectual disability. Preclinical studies show that the systemic administration of umbilical cord blood cells (UCBCs) is beneficial for neonatal HIE. We conducted a single-arm clinical study to examine the feasibility and safety of intravenous infusion of autologous UCBCs for newborns with HIE. When a neonate was born with severe asphyxia, the UCB was collected, volume-reduced, and divided into three doses. The processed UCB was infused at 12–24, 36–48, and 60–72 hours after the birth. The designed enrolment was six newborns. All six newborns received UCBC therapy strictly adhering to the study protocol together with therapeutic hypothermia. The physiological parameters and peripheral blood parameters did not change much between pre- and postinfusion. There were no serious adverse events that might be related to cell therapy. At 30 days of age, the six infants survived without circulatory or respiratory support. At 18 months of age, neurofunctional development was normal without any impairment in four infants and delayed with cerebral palsy in two infants. This pilot study shows that autologous UCBC therapy is feasible and safe.
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Affiliation(s)
- Masahiro Tsuji
- Department of Food and Nutrition, Kyoto Women's University, Kyoto, 605-8501, Japan.,Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, 565-8565, Japan
| | - Mariko Sawada
- Department of Pediatrics, Kurashiki Central Hospital, Kurashiki, 710-8602, Japan
| | - Shinichi Watabe
- Department of Pediatrics, Kurashiki Central Hospital, Kurashiki, 710-8602, Japan
| | - Hiroyuki Sano
- Department of Pediatrics, Yodogawa Christian Hospital, Osaka, 533-0024, Japan
| | - Masayo Kanai
- Division of Neonatology, Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe, 350-8850, Japan
| | - Emi Tanaka
- Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, 545-8585, Japan
| | - Satoshi Ohnishi
- Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, 545-8585, Japan
| | - Yoshiaki Sato
- Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, 466-8560, Japan
| | - Hisanori Sobajima
- Division of Neonatology, Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe, 350-8850, Japan
| | - Takashi Hamazaki
- Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, 545-8585, Japan
| | - Rintaro Mori
- Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan
| | - Akira Oka
- Department of Pediatrics, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Hiroyuki Ichiba
- Department of Neonatology, Osaka City General Hospital, Osaka, 534-0021, Japan
| | - Masahiro Hayakawa
- Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, 466-8560, Japan
| | - Satoshi Kusuda
- Department of Pediatrics, Kyorin University, Mitaka, 181-8611, Japan
| | - Masanori Tamura
- Division of Neonatology, Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe, 350-8850, Japan
| | - Makoto Nabetani
- Department of Pediatrics, Yodogawa Christian Hospital, Osaka, 533-0024, Japan.
| | - Haruo Shintaku
- Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, 545-8585, Japan.
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Zhao L, Sun W, Liang H, Gao T, Liu Y, Sun Y, Zhang S, Li C. Therapeutic effect of autologous bone marrow stem cell mobilization combined with anti-infective therapy on moyamoya disease. Saudi J Biol Sci 2019; 27:676-681. [PMID: 32210687 PMCID: PMC6997874 DOI: 10.1016/j.sjbs.2019.12.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 11/16/2019] [Accepted: 12/09/2019] [Indexed: 10/29/2022] Open
Abstract
Objective The purpose of this study is to explore the therapeutic effect of autologous bone marrow stem cell (ABMSC) mobilization combined anti-infection therapy on patients with moyamoya disease (MMD), and to provide reference for the clinical treatment of MMD and cerebrovascular disease. Methods 54 adult patients with MMD diagnosed in Henan Provincial People's Hospital from March 2017 to March 2019 were chosen as research objects. All patients were randomly divided into study group (SG) and control group (CG), with 27 patients in each group. Patients in both groups received conventional drug treatment after diagnosis of MMD, and received dura turnover of brain - temporal muscle - superficial temporal artery application surgery during indirect vascular reconstruction. On the basis of surgical treatment, patients in the SG were given ABMSC mobilization combined with low-dose dexamethasone for anti-inflammatory and anti-infection treatment. ABMSCs were mobilized by recombinant human granulocyte colony stimulating factor (rhG-csF) and recombinant human granulocyte - macrophage colony stimulating factor (rhoM-esF). The therapeutic effects of the patients were evaluated BF, one month after treatment (AF), three months AF, and six months AF. The number of hematopoietic stem cells (HpCs) and inflammatory indicators were compared between the two groups before and 4 weeks AF. Results Firstly, the Barthcl index of patients in the two groups showed a gradual increase trend at the 3rd and 6th months AF, and the ascensional range in the research group was higher than that in the CG (P < 0.05). Secondly, at the 3rd and 6th month AF, national institute of heath stroke scale (NIHSS) scores of patients in the CG were lower than those before treatment (BF), and there was an important change in NIHSS scores between the two groups at the same period (P < 0.05). Thirdly, after 1 month of treatment and 3 months of treatment, Chinese stroke scale (CSS) scores of patients in both groups decreased obviously compared with those BF, and the SG was lower than the CG, with statistical changes (P < 0.05). Fourthly, after 4 weeks of treatment, the hematopoietic stem cell counts in both groups were higher than those BF, and the hematopoietic stem cell counts in the SG were obviously higher than those in the CG (P < 0.05). All three inflammatory indicators were improved compared with those BF, and the SG was better than the CG (P < 0.05). Conclusion Autogenous bone marrow stem cell mobilization combined with dexamethasone anti-inflammation and anti-infection treatment after revascularization in patients with MMD can accelerate the recovery of nerve function and promote the formation of new blood vessels. At the same time, it can reduce inflammation and improve patients' quality of life, which is worthy of clinical reference.
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Affiliation(s)
- Liming Zhao
- Department of Neurosurgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan 450003, China
| | - Weiliang Sun
- Department of Neurosurgery, Henan University People's Hospital, Zhengzhou, Henan 450003, China
| | - Hao Liang
- Department of Neurosurgery, Henan University People's Hospital, Zhengzhou, Henan 450003, China
| | - Tao Gao
- Department of Neurosurgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan 450003, China
| | - Yang Liu
- Department of Neurosurgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan 450003, China
| | - Yuxue Sun
- Department of Neurosurgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan 450003, China
| | - Shao Zhang
- Department of Neurosurgery, Henan University People's Hospital, Zhengzhou, Henan 450003, China
| | - Chaoyue Li
- Department of Neurosurgery, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, Henan 450003, China
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Abstract
Cerebral palsy occurs more often in preterm than in term deliveries and is one of the major neurologic injuries seen in preterm infants. Magnesium sulfate has been found to reduce the risk of cerebral palsy in patients at risk of delivery before 32 weeks' gestational age. Multiple large clinical trials have shown this effect. The authors recommend magnesium sulfate bolus followed by continuous dosing of magnesium sulfate in those at risk of delivery before 32 weeks' gestation until delivery occurs or is no longer imminent. This article also discusses novel and emerging therapies for the prevention of cerebral palsy.
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Affiliation(s)
- Rebecca A Jameson
- Department of Obstetrics and Gynecology, The State University of New York Upstate Medical University, 750 East Adams Street, 2204 Weiskotten Hall, Syracuse, NY 13210, USA
| | - Helene B Bernstein
- Department of Obstetrics and Gynecology, The State University of New York Upstate Medical University, 750 East Adams Street, 2204 Weiskotten Hall, Syracuse, NY 13210, USA; Department of Microbiology and Immunology, The State University of New York Upstate Medical University, 750 East Adams Street, 2204 Weiskotten Hall, Syracuse, NY 13210, USA.
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Xue H, Xu Y, Wang S, Wu ZY, Li XY, Zhang YH, Niu JY, Gao QS, Zhao P. Sevoflurane post-conditioning alleviates neonatal rat hypoxic-ischemic cerebral injury via Ezh2-regulated autophagy. DRUG DESIGN DEVELOPMENT AND THERAPY 2019; 13:1691-1706. [PMID: 31190748 PMCID: PMC6528650 DOI: 10.2147/dddt.s197325] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 03/04/2019] [Indexed: 12/12/2022]
Abstract
Background: When neonatal rats suffer hypoxic-ischemic brain injury (HIBI), autophagy is over-activated in the hippocampus, and inhibition of autophagy provides neuroprotection. The aim of this study was to investigate the possible roles of autophagy and Ezh2-regulated Pten/Akt/mTOR pathway in sevoflurane post-conditioning (SPC)-mediated neuroprotection against HIBI in neonatal rats. Methods: Seven-day-old Sprague–Dawley rats underwent left common artery ligation followed by 2 h hypoxia as described in the Rice–Vannucci model. The roles of autophagy and the Ezh2-regulated Pten/Akt/mTOR signaling pathway in the neuroprotection conferred by SPC were examined by left-side intracerebroventricular injection with the autophagy activator rapamycin and the Ezh2 inhibitor GSK126. Results: SPC was neuroprotective against HIBI through the inhibition of over-activated autophagy in the hippocampus as characterized by the rapamycin-induced reversal of neuronal density, neuronal morphology, cerebral morphology, and the expression of the autophagy markers, LC3B-II and Beclin1. SPC significantly increased the expression of Ezh2, H3K27me3, pAkt, and mTOR and decreased the expression of Pten induced by HI. The Ezh2 inhibitor, GSK126, significantly reversed the SPC-induced changes in expression of H3K27me3, Pten, pAkt, mTOR, LC3B-II, and Beclin1. Ezh2 inhibition also reversed SPC-mediated attenuation of neuronal loss and behavioral improvement in the Morris water maze. Conclusion: These results indicate that SPC inhibits excessive autophagy via the regulation of Pten/Akt/mTOR signaling by Ezh2 to confer neuroprotection against HIBI in neonatal rats.
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Affiliation(s)
- Hang Xue
- Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang 110004, People's Republic of China
| | - Ying Xu
- Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang 110004, People's Republic of China
| | - Shuo Wang
- Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang 110004, People's Republic of China
| | - Zi-Yi Wu
- Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang 110004, People's Republic of China
| | - Xing-Yue Li
- Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang 110004, People's Republic of China
| | - Ya-Han Zhang
- Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang 110004, People's Republic of China
| | - Jia-Yuan Niu
- Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang 110004, People's Republic of China
| | - Qiu-Shi Gao
- Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang 110004, People's Republic of China
| | - Ping Zhao
- Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang 110004, People's Republic of China
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Wang G, Guo H, Wang X. Platycodin D protects cortical neurons against oxygen-glucose deprivation/reperfusion in neonatal hypoxic-ischemic encephalopathy. J Cell Biochem 2019; 120:14028-14034. [PMID: 30945345 DOI: 10.1002/jcb.28677] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Revised: 02/10/2019] [Accepted: 02/14/2019] [Indexed: 12/29/2022]
Abstract
Neonatal hypoxic-ischemic encephalopathy is one of the leading causes of death in infants. Increasing evidence indicates that oxidative stress and apoptosis are major contributors to hypoxic-ischemic injury and can be used as particularly promising therapeutic targets. Platycodin D (PLD) is a triterpenoid saponin that exhibits antioxidant properties. The aim of this study was to evaluate the effects of PLD on hypoxic-ischemic injury in primary cortical neurons. We found that oxygen-glucose deprivation/reperfusion (OGD/R) induced inhibition of cell viability and cytotoxicity, which were attenuated by PLD treatment. PLD treatment inhibited oxidative stress induced by OGD/R, which was evidenced by the reduced level of reactive oxygen species and increased activities of catalase, superoxide dismutase, and glutathione peroxidase. Histone-DNA enzyme-linked immunosorbent assay revealed that apoptosis was significantly decreased after PLD treatment in OGD/R-treated cortical neurons. The increased bax expression and decreased bcl-2 expression induced by OGD/R were reversed by PLD treatment. Furthermore, PLD treatment caused the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway in OGD/R-stimulated cortical neurons. Suppression of this pathway blocked the protective effects of PLD on OGD/R-induced cell injury. These findings suggested that PLD executes its protective effects on OGD/R-induced cell injury via regulating the PI3K/Akt/mTOR pathway in cortical neurons.
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Affiliation(s)
- Guifang Wang
- Department of Pediatrics, Xinxiang Central Hospital, Xinxiang, Henan, China
| | - Hongxiang Guo
- Department of Neonatal Pediatrics, The First Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xiaofang Wang
- Department of Pediatrics, Xinxiang Central Hospital, Xinxiang, Henan, China
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The neurorestorative effect of human amniotic fluid stem cells on the chronic phase of neonatal hypoxic-ischemic encephalopathy in mice. Pediatr Res 2019; 85:97-104. [PMID: 30120407 DOI: 10.1038/s41390-018-0131-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 06/25/2018] [Accepted: 07/22/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND Hypoxic-ischemic encephalopathy (HIE) remains a major cause of cerebral palsy. Increasing evidence has suggested that mesenchymal stem cells have a favorable effect on HIE. However, the efficacy of human amniotic fluid stem cells (hAFS) for HIE, especially in the chronic phase, remains unclear. The aim of this study was to determine the neurorestorative effect of hAFS on the chronic phase of HIE. METHODS hAFS were isolated from AF cells as CD117-positive cells. HI was induced in 9-day-old mice. Animals intranasally received hAFS or phosphate-buffered saline at 10 days post HI and were harvested for histological analysis after functional tests at 21 days post HI. We also implanted PKH26-positive hAFS to assess their migration to the brain. Finally, we determined gene expressions of trophic factors in hAFS co-cultured with HI brain extract. RESULTS hAFS improved sensorimotor deficits in HIE by gray and white matter restoration and neuroinflammation reduction followed by migration to the lesion. Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), hepatocyte growth factor (HGF), and stromal cell-derived factor-1 (SDF-1) gene expressions in hAFS were elevated when exposed to HI-induced brain extract. CONCLUSION hAFS induced functional recovery by exerting neurorestorative effects in HIE mice, suggesting that intranasal administration of hAFS could be a novel treatment for HIE, especially in the chronic phase.
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Bruschettini M, Romantsik O, Moreira A, Ley D, Thébaud B. Stem cell-based interventions for the prevention of morbidity and mortality following hypoxic-ischaemic encephalopathy in newborn infants. Hippokratia 2018. [DOI: 10.1002/14651858.cd013202] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Matteo Bruschettini
- Lund University, Skåne University Hospital; Department of Paediatrics; Lund Sweden
- Skåne University Hospital; Cochrane Sweden; Wigerthuset, Remissgatan 4, first floor room 11-221 Lund Sweden 22185
| | - Olga Romantsik
- Lund University, Skåne University Hospital; Department of Paediatrics; Lund Sweden
| | - Alvaro Moreira
- University of Texas Health Science Center at San Antonio; Pediatrics, Division of Neonatology; San Antonio Texas USA
| | - David Ley
- Lund University, Skåne University Hospital; Department of Paediatrics; Lund Sweden
| | - Bernard Thébaud
- Children's Hospital of Eastern Ontario; Department of Pediatrics; Ottawa ON Canada
- Ottawa Hospital Research Institute, Sprott Center for Stem Cell Research; Ottawa Canada
- University of Ottawa; Department of Cellular and Molecular Medicine; Ottawa Canada
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Jiao Y, Li XY, Liu J. A New Approach to Cerebral Palsy Treatment: Discussion of the Effective Components of Umbilical Cord Blood and its Mechanisms of Action. Cell Transplant 2018; 28:497-509. [PMID: 30384766 PMCID: PMC7103597 DOI: 10.1177/0963689718809658] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cerebral palsy (CP) includes a group of persistent non-progressive disorders
affecting movement, muscle tone, and/or posture. The total economic loss during
the life-span of an individual with CP places a heavy financial burden on such
patients and their families worldwide; however, a complete cure is still
lacking. Umbilical cord blood (UCB)-based interventions are emerging as a
scientifically plausible treatment and possible cure for CP. Stem cells have
been used in many experimental CP animal models and achieved good results.
Compared with other types of stem cells, those from UCB have advantages in terms
of treatment safety and efficacy, ethics, non-neoplastic proliferation,
accessibility, ease of preservation, and regulation of immune responses, based
on findings in animal models and clinical trials. Currently, the use of
UCB-based interventions for CP is limited as the components of UCB are complex
and possess different therapeutic mechanisms. These can be categorized by three
aspects: homing and neuroregeneration, trophic factor secretion, and
neuroprotective effects. Our review summarizes the features of active components
of UCB and their therapeutic mechanism of action. This review highlights current
research findings and clinical evidence regarding UCB that contribute to
treatment suggestions, inform decision-making for therapeutic interventions, and
help to direct future research.
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Affiliation(s)
- Yang Jiao
- 1 Stem Cell Clinical Research Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Xiao-Yan Li
- 1 Stem Cell Clinical Research Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China
| | - Jing Liu
- 1 Stem Cell Clinical Research Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P.R. China
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Ma W, Xie X, Shao X, Zhang Y, Mao C, Zhan Y, Zhao D, Liu M, Li Q, Lin Y. Tetrahedral DNA nanostructures facilitate neural stem cell migration via activating RHOA/ROCK2 signalling pathway. Cell Prolif 2018; 51:e12503. [PMID: 30091500 DOI: 10.1111/cpr.12503] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Accepted: 06/20/2018] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES The main purpose of current study was to explore the effects of tetrahedral DNA nanostructures (TDNs) on neuroectodermal (NE-4C) stem cells migration and unveil the potential mechanisms. MATERIALS AND METHODS The successfully self-assembled TDNs were also determined by dynamic light scattering (DLS). A bidirectional wound-healing assay and transwell chamber assay were employed to test the migrating behaviour of NE-4C stem cells cultured under different conditions. RESULTS Through an in vitro study, we found that stem cells could internalize TDNs quickly, and the cells' parallel and vertical migration was promoted effectively. Besides, the effects of TDNs were found being exerted by upregulating the gene and protein expression levels of RhoA, Rock2 and Vinculin, indicating that the RHOA/ROCK2 pathway was activated by the TDNs during the cell migration. CONCLUSIONS In conclusion, TDNs could enter NSCs without the aid of other transfection reagents in large amounts, whereas only small amounts of ssDNA could enter the cells. TDNs taken up by NSCs activated the RHOA/ROCK2 signalling pathway, which had effects on the relevant genes and proteins expression, eventually promoting the migration of NE-4C stem cells. These findings suggested that TDNs have great potential in application for the repair and regeneration of neural tissue.
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Affiliation(s)
- Wenjuan Ma
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xueping Xie
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Xiaoru Shao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yuxin Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chenchen Mao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yuxi Zhan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Dan Zhao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Mengting Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Qianshun Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yunfeng Lin
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Nair J, Kumar VHS. Current and Emerging Therapies in the Management of Hypoxic Ischemic Encephalopathy in Neonates. CHILDREN (BASEL, SWITZERLAND) 2018; 5:E99. [PMID: 30029531 PMCID: PMC6069156 DOI: 10.3390/children5070099] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Revised: 07/09/2018] [Accepted: 07/16/2018] [Indexed: 01/01/2023]
Abstract
Neonatal hypoxic ischemic encephalopathy (HIE) presents a significant clinical burden with its high mortality and morbidity rates globally. Therapeutic hypothermia (TH) is now standard of care for infants with moderate to severe HIE, but has not definitively changed outcomes in severe HIE. In this review, we discuss newer promising markers that may help the clinician identify severity of HIE. Therapies that are beneficial and agents that hold promise for neuroprotection are described, both for use either alone or as adjuncts to TH. These include endogenous pathway modifiers such as erythropoietin and analogues, melatonin, and remote ischemic post conditioning. Stem cells have therapeutic potential in this condition, as in many other neonatal conditions. Of the agents listed, only erythropoietin and analogues are currently being evaluated in large randomized controlled trials (RCTs). Exogenous therapies such as argon and xenon, allopurinol, monosialogangliosides, and magnesium sulfate continue to be investigated. The recognition of tertiary mechanisms of brain damage has opened up new research into therapies not only to attenuate brain damage but also to promote cell repair and regeneration in a developmentally disorganized brain long after the perinatal insult. These alternative modalities may be especially important in mild HIE and in areas of the world where there is limited access to expensive hypothermia equipment and services.
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Affiliation(s)
- Jayasree Nair
- Division of Neonatology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA.
| | - Vasantha H S Kumar
- Division of Neonatology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA.
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Ma W, Shao X, Zhao D, Li Q, Liu M, Zhou T, Xie X, Mao C, Zhang Y, Lin Y. Self-Assembled Tetrahedral DNA Nanostructures Promote Neural Stem Cell Proliferation and Neuronal Differentiation. ACS APPLIED MATERIALS & INTERFACES 2018; 10:7892-7900. [PMID: 29424522 DOI: 10.1021/acsami.8b00833] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Stem cell-based therapy is considered a promising approach for the repair of nervous tissues. Neural stem cells (NSCs) cannot proliferate or differentiate efficiently; hence, different biomaterials have been explored to improve NSC proliferation and differentiation. However, these agents either had low bioavailability or poor biocompatibility. In this work, our group investigated the effects of tetrahedral DNA nanostructures (TDNs), a novel DNA biological material, on the self-renew and differentiation of neuroectodermal (NE-4C) stem cells. We observed that TDN treatment promoted self-renew of the stem cells via activating the Wnt/β -catenin pathway. In addition, our findings suggested that NE-4C stem cells' neuronal differentiation could be promoted effectively by TDNs via inhibiting the notch signaling pathway. In summary, this is the first report about the effects of TDNs on the proliferation and differentiation of NE-4C stem cells and the results demonstrate that TDNs have a great potential in nerve tissue regeneration.
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Affiliation(s)
- Wenjuan Ma
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology , Sichuan University , Chengdu 610041 , P. R. China
| | - Xiaoru Shao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology , Sichuan University , Chengdu 610041 , P. R. China
| | - Dan Zhao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology , Sichuan University , Chengdu 610041 , P. R. China
| | - Qianshun Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology , Sichuan University , Chengdu 610041 , P. R. China
| | - Mengting Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology , Sichuan University , Chengdu 610041 , P. R. China
| | - Tengfei Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology , Sichuan University , Chengdu 610041 , P. R. China
| | - Xueping Xie
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology , Sichuan University , Chengdu 610041 , P. R. China
| | - Chenchen Mao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology , Sichuan University , Chengdu 610041 , P. R. China
| | - Yuxin Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology , Sichuan University , Chengdu 610041 , P. R. China
| | - Yunfeng Lin
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology , Sichuan University , Chengdu 610041 , P. R. China
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