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Smeets LC, Sengun E, Trayford C, van Cranenbroek B, de Jonge MI, Dallaglio K, Hütten MC, Schoberer M, Ophelders DRMG, Wolfs TGAM, van der Molen RG, van Rijt S. Gold Mesoporous Silica-Coated Nanoparticles for Quantifying and Qualifying Mesenchymal Stem Cell Distribution; a Proof-of-Concept Study in Large Animals. ACS APPLIED BIO MATERIALS 2025; 8:1511-1523. [PMID: 39900538 PMCID: PMC11836931 DOI: 10.1021/acsabm.4c01714] [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: 11/14/2024] [Revised: 01/21/2025] [Accepted: 01/23/2025] [Indexed: 02/05/2025]
Abstract
Mesenchymal stem cells (MSCs) have demonstrated promising therapeutic potential across a wide range of diseases including (multi) organ injury in neonates. Despite the reported preclinical successes of MSC therapy, a major challenge in their clinical translation is a limited understanding of their biodistribution after administration. This knowledge gap needs to be addressed to allow clinical implementation. Accordingly, in this study, we propose that silica-coated gold nanoparticles (AuMS) are a promising tool for in vivo MSC tracing. This study explores the use of AuMS for both qualitative and quantitative MSC tracking in vivo after intravenous (I.V.) administration in a translational ovine model of preterm birth. Additionally, we assess the impact of AuMS labeling on the immunomodulatory functions of MSC, which play an important role in the therapeutic potency of these cells. Quantitative and qualitative assessment of AuMS-labeled MSC was performed in vivo using fluorescent microscopy and inductively coupled plasma mass spectrometry (ICP-MS), respectively. AuMS localization in the liver, spleen, and lung was demonstrated. In vitro studies showed that AuMS cellular uptake occurs within 6 h and remains internalized up to 72 h. Labeled MSC maintained their immune phenotype and did not alter their immunomodulatory capacity and proliferation abilities. Overall, we demonstrate that AuMS is a promising, biocompatible nanoprobe for MSC tracing up to 72 h post-I.V. administration.
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Affiliation(s)
- Lotte
C. C. Smeets
- MERLN
Institute for Technology-Inspired Regenerative Medicine, Maastricht University, P.O. Box 616, Maastricht 6200 MD, The Netherlands
- Department
of Pediatrics, Maastricht University Medical
Center+, MosaKids Children’s Hospital, Maastricht 6200 MD, The Netherlands
- GROW
Research Institute for Oncology and Reproduction, Maastricht University, Maastricht 6200 MD, The Netherlands
| | - Ezgi Sengun
- Department
of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center Nijmegen, Nijmegen 6500 HB, The Netherlands
| | - Chloe Trayford
- MERLN
Institute for Technology-Inspired Regenerative Medicine, Maastricht University, P.O. Box 616, Maastricht 6200 MD, The Netherlands
| | - Bram van Cranenbroek
- Department
of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center Nijmegen, Nijmegen 6500 HB, The Netherlands
| | - Marien I. de Jonge
- Department
of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center Nijmegen, Nijmegen 6500 HB, The Netherlands
| | | | - Matthias C. Hütten
- Department
of Pediatrics, Maastricht University Medical
Center+, MosaKids Children’s Hospital, Maastricht 6200 MD, The Netherlands
- GROW
Research Institute for Oncology and Reproduction, Maastricht University, Maastricht 6200 MD, The Netherlands
| | - Mark Schoberer
- Division
of Neonatology, Department of Pediatrics, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Daan R. M. G. Ophelders
- Department
of Pediatrics, Maastricht University Medical
Center+, MosaKids Children’s Hospital, Maastricht 6200 MD, The Netherlands
- GROW
Research Institute for Oncology and Reproduction, Maastricht University, Maastricht 6200 MD, The Netherlands
| | - Tim G. A. M. Wolfs
- Department
of Pediatrics, Maastricht University Medical
Center+, MosaKids Children’s Hospital, Maastricht 6200 MD, The Netherlands
- GROW
Research Institute for Oncology and Reproduction, Maastricht University, Maastricht 6200 MD, The Netherlands
| | - Renate G. van der Molen
- Department
of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center Nijmegen, Nijmegen 6500 HB, The Netherlands
| | - Sabine van Rijt
- MERLN
Institute for Technology-Inspired Regenerative Medicine, Maastricht University, P.O. Box 616, Maastricht 6200 MD, The Netherlands
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Saneh H, Wanczyk H, Walker J, Finck C. Stem cell-derived extracellular vesicles: a potential intervention for Bronchopulmonary Dysplasia. Pediatr Res 2025; 97:497-509. [PMID: 39251881 PMCID: PMC12014501 DOI: 10.1038/s41390-024-03471-2] [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: 02/01/2024] [Revised: 06/06/2024] [Accepted: 07/16/2024] [Indexed: 09/11/2024]
Abstract
Despite advances in neonatal care, the incidence of Bronchopulmonary Dysplasia (BPD) remains high among extreme preterm infants. The pathogenesis of BPD is multifactorial, with inflammation playing a central role. There is strong evidence that stem cell therapy reduces inflammatory changes and restores normal lung morphology in animal models of hyperoxia-induced lung injury. These therapeutic effects occur without significant engraftment of the stem cells in the host lung, suggesting more of a paracrine mechanism mediated by their secretome. In addition, there are multiple concerns with stem cell therapy which may be alleviated by administering only the effective vesicles instead of the cells themselves. Extracellular vesicles (EVs) are cell-derived components secreted by most eukaryotic cells. They can deliver their bioactive cargo (mRNAs, microRNAs, proteins, growth factors) to recipient cells, which makes them a potential therapeutic vehicle in many diseases, including BPD. The following review will highlight recent studies that investigate the effectiveness of EVs derived from stem cells in preventing or repairing injury in the preterm lung, and the potential mechanisms of action that have been proposed. Current limitations will also be discussed as well as suggestions for advancing the field and easing the transition towards clinical translation in evolving or established BPD. IMPACT: Extracellular vesicles (EVs) derived from stem cells are a potential intervention for neonatal lung diseases. Their use might alleviate the safety concerns associated with stem cell therapy. This review highlights recent studies that investigate the effectiveness of stem cell-derived EVs in preclinical models of bronchopulmonary dysplasia. It adds to the existing literature by elaborating on the challenges associated with EV research. It also provides suggestions to advance the field and ease the transition towards clinical applications. Optimizing EV research could ultimately improve the quality of life of extreme preterm infants born at vulnerable stages of lung development.
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Affiliation(s)
- Hala Saneh
- Department of Neonatal Medicine, Connecticut Children's Medical Center, Hartford, CT, USA.
- Department of Pediatrics, University of Connecticut Health Center, Farmington, CT, USA.
| | - Heather Wanczyk
- Department of Pediatrics, University of Connecticut Health Center, Farmington, CT, USA
| | - Joanne Walker
- Department of Pediatrics, University of Connecticut Health Center, Farmington, CT, USA
| | - Christine Finck
- Department of Pediatrics, University of Connecticut Health Center, Farmington, CT, USA
- Department of Pediatric Surgery, Connecticut Children's Medical Center, Hartford, CT, USA
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Rahimi Darehbagh R, Seyedoshohadaei SA, Ramezani R, Rezaei N. Stem cell therapies for neurological disorders: current progress, challenges, and future perspectives. Eur J Med Res 2024; 29:386. [PMID: 39054501 PMCID: PMC11270957 DOI: 10.1186/s40001-024-01987-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 07/17/2024] [Indexed: 07/27/2024] Open
Abstract
Stem cell-based therapies have emerged as a promising approach for treating various neurological disorders by harnessing the regenerative potential of stem cells to restore damaged neural tissue and circuitry. This comprehensive review provides an in-depth analysis of the current state of stem cell applications in primary neurological conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other related disorders. The review begins with a detailed introduction to stem cell biology, discussing the types, sources, and mechanisms of action of stem cells in neurological therapies. It then critically examines the preclinical evidence from animal models and early human trials investigating the safety, feasibility, and efficacy of different stem cell types, such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs). While ESCs have been studied extensively in preclinical models, clinical trials have primarily focused on adult stem cells such as MSCs and NSCs, as well as iPSCs and their derivatives. We critically assess the current state of research for each cell type, highlighting their potential applications and limitations in different neurological conditions. The review synthesizes key findings from recent, high-quality studies for each neurological condition, discussing cell manufacturing, delivery methods, and therapeutic outcomes. While the potential of stem cells to replace lost neurons and directly reconstruct neural circuits is highlighted, the review emphasizes the critical role of paracrine and immunomodulatory mechanisms in mediating the therapeutic effects of stem cells in most neurological disorders. The article also explores the challenges and limitations associated with translating stem cell therapies into clinical practice, including issues related to cell sourcing, scalability, safety, and regulatory considerations. Furthermore, it discusses future directions and opportunities for advancing stem cell-based treatments, such as gene editing, biomaterials, personalized iPSC-derived therapies, and novel delivery strategies. The review concludes by emphasizing the transformative potential of stem cell therapies in revolutionizing the treatment of neurological disorders while acknowledging the need for rigorous clinical trials, standardized protocols, and multidisciplinary collaboration to realize their full therapeutic promise.
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Affiliation(s)
- Ramyar Rahimi Darehbagh
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Nanoclub Elites Association, Tehran, Iran
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Universal Scientific Education and Research Network (USERN), Sanandaj, Kurdistan, Iran
| | | | - Rojin Ramezani
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Goryunov K, Ivanov M, Kulikov A, Shevtsova Y, Burov A, Podurovskaya Y, Zubkov V, Degtyarev D, Sukhikh G, Silachev D. A Review of the Use of Extracellular Vesicles in the Treatment of Neonatal Diseases: Current State and Problems with Translation to the Clinic. Int J Mol Sci 2024; 25:2879. [PMID: 38474125 PMCID: PMC10932115 DOI: 10.3390/ijms25052879] [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: 01/15/2024] [Revised: 02/22/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024] Open
Abstract
Neonatal disorders, particularly those resulting from prematurity, pose a major challenge in health care and have a significant impact on infant mortality and long-term child health. The limitations of current therapeutic strategies emphasize the need for innovative treatments. New cell-free technologies utilizing extracellular vesicles (EVs) offer a compelling opportunity for neonatal therapy by harnessing the inherent regenerative capabilities of EVs. These nanoscale particles, secreted by a variety of organisms including animals, bacteria, fungi and plants, contain a repertoire of bioactive molecules with therapeutic potential. This review aims to provide a comprehensive assessment of the therapeutic effects of EVs and mechanistic insights into EVs from stem cells, biological fluids and non-animal sources, with a focus on common neonatal conditions such as hypoxic-ischemic encephalopathy, respiratory distress syndrome, bronchopulmonary dysplasia and necrotizing enterocolitis. This review summarizes evidence for the therapeutic potential of EVs, analyzes evidence of their mechanisms of action and discusses the challenges associated with the implementation of EV-based therapies in neonatal clinical practice.
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Affiliation(s)
- Kirill Goryunov
- V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow 117198, Russia; (K.G.); (M.I.); (Y.S.); (A.B.); (Y.P.); (V.Z.); (D.D.); (G.S.)
| | - Mikhail Ivanov
- V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow 117198, Russia; (K.G.); (M.I.); (Y.S.); (A.B.); (Y.P.); (V.Z.); (D.D.); (G.S.)
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia
| | - Andrey Kulikov
- Medical Institute, Patrice Lumumba Peoples’ Friendship University of Russia (RUDN University), Moscow 117198, Russia;
| | - Yulia Shevtsova
- V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow 117198, Russia; (K.G.); (M.I.); (Y.S.); (A.B.); (Y.P.); (V.Z.); (D.D.); (G.S.)
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia
| | - Artem Burov
- V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow 117198, Russia; (K.G.); (M.I.); (Y.S.); (A.B.); (Y.P.); (V.Z.); (D.D.); (G.S.)
| | - Yulia Podurovskaya
- V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow 117198, Russia; (K.G.); (M.I.); (Y.S.); (A.B.); (Y.P.); (V.Z.); (D.D.); (G.S.)
| | - Victor Zubkov
- V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow 117198, Russia; (K.G.); (M.I.); (Y.S.); (A.B.); (Y.P.); (V.Z.); (D.D.); (G.S.)
| | - Dmitry Degtyarev
- V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow 117198, Russia; (K.G.); (M.I.); (Y.S.); (A.B.); (Y.P.); (V.Z.); (D.D.); (G.S.)
| | - Gennady Sukhikh
- V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow 117198, Russia; (K.G.); (M.I.); (Y.S.); (A.B.); (Y.P.); (V.Z.); (D.D.); (G.S.)
| | - Denis Silachev
- V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow 117198, Russia; (K.G.); (M.I.); (Y.S.); (A.B.); (Y.P.); (V.Z.); (D.D.); (G.S.)
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia
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Lehnerer V, Roidl A, Romantsik O, Guzman R, Wellmann S, Bruschettini M. Mesenchymal stem cell therapy in perinatal arterial ischemic stroke: systematic review of preclinical studies. Pediatr Res 2024; 95:18-33. [PMID: 35906311 PMCID: PMC10798891 DOI: 10.1038/s41390-022-02208-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 06/30/2022] [Accepted: 07/06/2022] [Indexed: 12/22/2022]
Abstract
BACKGROUND Perinatal arterial ischemic stroke (PAIS) is a neurologic disorder leading to long-term complications. Mesenchymal stem cells (MSCs) have emerged as a novel therapeutic agent. This systematic review aims to determine the effects of stem cell-based interventions for the treatment of PAIS in preclinical studies. METHODS We included all controlled studies on MSCs in neonatal animals with PAIS. Functional outcome was the primary outcome. The literature search was performed in February 2021. RESULTS In the 20 included studies, MSCs were most frequently delivered via intracerebral injection (n = 9), 3 days after the induction of PAIS (n = 8), at a dose ranging from 5 × 104 to 5 × 106 cells. The meta-analysis showed an improvement on the cylinder rearing test (MD: -10.62; 95% CI: -14.38 to -6.86) and on the water maze test (MD: 1.31 MD; 95% CI: 0.80 to 1.81) in animals treated with MSCs compared to the control group animals. CONCLUSION MSCs appear to improve sensorimotor and cognitive performance in PAIS-injured animals; however, the certainty of the evidence is low. Registration of the protocol of preclinical studies, appropriate sample size calculation, rigorous randomization, and reporting of the data on animal sex and survival are warranted. PROSPERO registration number: CRD42021239642. IMPACT This is the first systematic review and meta-analysis of preclinical studies investigating the effects of MSCs in an experimental model of PAIS. MSCs appear to improve sensorimotor and cognitive performance in PAIS-injured neonatal animals. The certainty of the evidence is low due to high or unclear risk of bias in most domains.
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Affiliation(s)
- Verena Lehnerer
- Department of Neonatology, University Children's Hospital Regensburg (KUNO) at the Hospital St. Hedwig of the Order of St. John, University of Regensburg, Regensburg, Germany
| | - Anna Roidl
- Department of Neonatology, University Children's Hospital Regensburg (KUNO) at the Hospital St. Hedwig of the Order of St. John, University of Regensburg, Regensburg, Germany
| | - Olga Romantsik
- Department of Clinical Sciences Lund, Paediatrics, Lund University, Skåne University Hospital, Lund, Sweden
| | - Raphael Guzman
- Faculty of Medicine, University of Basel, 4056, Basel, Switzerland
- Department of Neurosurgery, University Hospital Basel, 4031, Basel, Switzerland
| | - Sven Wellmann
- Department of Neonatology, University Children's Hospital Regensburg (KUNO) at the Hospital St. Hedwig of the Order of St. John, University of Regensburg, Regensburg, Germany
| | - Matteo Bruschettini
- Department of Clinical Sciences Lund, Paediatrics, Lund University, Skåne University Hospital, Lund, Sweden.
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Hladkykh FV. MESENCHYMAL STEM CELLS: EXOSOMES AND CONDITIONED MEDIA AS INNOVATIVE STRATEGIES IN THE TREATMENT OF PATIENTS WITH AUTOIMMUNE DISEASES. CLINICAL AND PREVENTIVE MEDICINE 2023:121-130. [DOI: 10.31612/2616-4868.6.2023.15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Introduction. Autoimmune diseases are a class of immunopathological conditions heterogeneous in clinical manifestations, characterized by immune disorders that cause the loss of the body's autoimmune tolerance and, as a result, abnormal reactivity of B-cells and T-cells, which leads to damage to own tissues. Today, about 10% of the population suffers from diseases of this class, which are clinically manifested in the form of more than 80 forms of autoimmune diseases.
The aim of the study. Summarize current ideas about the therapeutic potential of conditioned media and exosomes of MSCs in the treatment of patients with autoimmune diseases based on data from open sources of information.
Materials and methods. Publications were selected based on PubMed, Clinical Key Elsevier, Cochrane Library, eBook Business Collection and Google Scholar databases, which covered information on the use of conditioned media and MSC exosomes in the treatment of diseases of premature newborns using the
Keywords:
mesenchymal stem cells, conditioned media, secretion, autoimmune diseases.
Results. The technical complexity and high costs associated with the production and regulatory approval procedures of MSC therapy create barriers to their clinical use. Studies have shown that the cell-free secretome of MSCs, which consists of a wide range of growth factors, cytokines, chemokines and extracellular vesicles, exhibits a pluripotent effect. Today, extracellular vesicles are classified according to their diameter into apoptotic bodies (>1000 nm), microvesicles (100–1000 nm) and exosomes (30–150 nm). Exosome activity can be easily manipulated by preconditioning MSCs, by simply adding cytokines or chemicals to the culture medium, by introducing gene modifications, or by using hypoxic culture conditions. A number of studies have demonstrated the comparable effectiveness of conditioned media and MSC exosomes in the treatment of patients with autoimmune diseases.
Conclusions. Exosomes and conditioned media with MSCs have the potential to replace cell therapy or serve as a comparable clinical strategy to biological therapy in neonatology. MSC preconditioning will allow modulating the therapeutic effects of exosomes and will become the basis for establishing recommendations and standards for effective and safe cell-free therapy.
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Mesfin FM, Manohar K, Shelley WC, Brokaw JP, Liu J, Ma M, Markel TA. Stem cells as a therapeutic avenue for active and long-term complications of Necrotizing Enterocolitis. Semin Pediatr Surg 2023; 32:151311. [PMID: 37276782 PMCID: PMC10330659 DOI: 10.1016/j.sempedsurg.2023.151311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Necrotizing enterocolitis (NEC) is a devastating neonatal intestinal disease associated with significant morbidity and mortality. Although decades of research have been dedicated to understanding the pathogenesis of NEC and developing therapies, it remains the leading cause of death among neonatal gastrointestinal diseases. Mesenchymal stem cells (MSCs) have garnered significant interest recently as potential therapeutic agents for the treatment of NEC. They have been shown to rescue intestinal injury and reduce the incidence and severity of NEC in various preclinical animal studies. MSCs and MSC-derived organoids and tissue engineered small intestine (TESI) have shown potential for the treatment of long-term sequela of NEC such as short bowel syndrome, neurodevelopmental delay, and chronic lung disease. Although the advances made in the use of MSCs are promising, further research is needed prior to the widespread use of these cells for the treatment of NEC.
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Affiliation(s)
- Fikir M Mesfin
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Krishna Manohar
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - W Christopher Shelley
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - John P Brokaw
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jianyun Liu
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Minglin Ma
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA
| | - Troy A Markel
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN, USA; Riley Hospital for Children at Indiana University Health, Indianapolis, IN, USA.
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Huang P, Qin X, Fan C, Wang M, Chen F, Liao M, Zhong H, Wang H, Ma L. Comparison of Biological Characteristics of Human Umbilical Cord Wharton's Jelly-Derived Mesenchymal Stem Cells from Extremely Preterm and Term Infants. Tissue Eng Regen Med 2023:10.1007/s13770-023-00538-9. [PMID: 37249837 DOI: 10.1007/s13770-023-00538-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 02/21/2023] [Accepted: 03/14/2023] [Indexed: 05/31/2023] Open
Abstract
BACKGROUND Despite the progress in perinatal-neonatal medicine, complications of extremely preterm infants continue to constitute the major adverse outcomes in neonatal intensive care unit. Human umbilical cord Wharton's Jelly-derived mesenchymal stem cells (HUMSCs) may offer new hope for the treatment of intractable neonatal disorders. This study will explore the functional differences of HUMSCs between extremely preterm and term infants. METHODS UMSCs from 5 extremely preterm infants(weeks of gestation: 22+5 w,24+4 w,25+3 w,26 w,28 w) and 2 term infants(39 w,39+2 w) were isolated, and mesenchymal markers, pluripotent genes, proliferation rate were analyzed. HUVECs were injured by treated with LPS and repaired by co-cultured with HUMSCs of different gestational ages. RESULTS All HUMSCs showed fibroblast-like adherence to plastic and positively expressed surface marker of CD105,CD73 and CD90, but did not expressed CD45,CD34,CD14,CD79a and HLA-DR; HUMSCs in extremely preterm exhibited significant increase in proliferation as evidenced by CCK8, pluripotency markers OCT-4 tested by RT-PCR also showed increase. Above all, in LPS induced co-cultured inflame systerm, HUMSCs in extremely preterm were more capable to promote wound healing and tube formation in HUVEC cultures, they promoted TGFβ1 expression and inhibited IL6 expression. CONCLUSIONS Our results suggest that HUMSCs from extremely preterm infants may be more suitable as candidates in cell therapy for the preterm infants.
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Affiliation(s)
- Peng Huang
- Shenzhen Children's Hospital of China Medical University, Shenzhen, 518038, China
- Affiliated Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, 518028, China
| | - Xiaofei Qin
- Shenzhen People's Hospital, Shenzhen, 518020, China
| | - Chuiqin Fan
- Shenzhen Children's Hospital of China Medical University, Shenzhen, 518038, China
| | - Manna Wang
- Department of Pediatrics, The Women and Children's Medical Hospital of Guangzhou Medical University, The Third Affifiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Fuyi Chen
- Department of Pediatrics, The Women and Children's Medical Hospital of Guangzhou Medical University, The Third Affifiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Maochuan Liao
- Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Huifeng Zhong
- Affiliated Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, 518028, China
| | - Hongwu Wang
- Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China.
| | - Lian Ma
- Shenzhen Children's Hospital of China Medical University, Shenzhen, 518038, China.
- Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China.
- Department of Pediatrics, The Women and Children's Medical Hospital of Guangzhou Medical University, The Third Affifiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
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9
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Mesfin FM, Manohar K, Hunter CE, Shelley WC, Brokaw JP, Liu J, Ma M, Markel TA. Stem cell derived therapies to preserve and repair the developing intestine. Semin Perinatol 2023; 47:151727. [PMID: 36964032 PMCID: PMC10133028 DOI: 10.1016/j.semperi.2023.151727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/26/2023]
Abstract
Stem cell research and the use of stem cells in therapy have seen tremendous growth in the last two decades. Neonatal intestinal disorders such as necrotizing enterocolitis, Hirschsprung disease, and gastroschisis have high morbidity and mortality and limited treatment options with varying success rates. Stem cells have been used in several pre-clinical studies to address various neonatal disorders with promising results. Stem cell and patient population selection, timing of therapy, as well as safety and quality control are some of the challenges that must be addressed prior to the widespread clinical application of stem cells. Further research and technological advances such as the use of cell delivery technology can address these challenges and allow for continued progress towards clinical translation.
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Affiliation(s)
- Fikir M Mesfin
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Krishna Manohar
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Chelsea E Hunter
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - W Christopher Shelley
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - John P Brokaw
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Jianyun Liu
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Minglin Ma
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY
| | - Troy A Markel
- Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine, Indianapolis, IN; Riley Hospital for Children at Indiana University Health, Indianapolis, IN.
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10
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Damianos A, Sammour I. Barriers in translating stem cell therapies for neonatal diseases. Semin Perinatol 2023; 47:151731. [PMID: 36990922 DOI: 10.1016/j.semperi.2023.151731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
Abstract
Over the last 20 years, stem cells of varying origin and their associated secretome have been investigated as a therapeutic option for a myriad of neonatal models of disease, with very promising results. Despite the devastating nature of some of these disorders, translation of the preclinical evidence to the bedside has been slow. In this review, we explore the existing clinical evidence for stem cell therapies in neonates, highlight the barriers faced by researchers and suggest potential solutions to move the field forward.
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Affiliation(s)
- Andreas Damianos
- Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, Ohio
| | - Ibrahim Sammour
- Riley Hospital for Children, Indiana University, Indianapolis, USA.
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Provitera L, Tomaselli A, Raffaeli G, Crippa S, Arribas C, Amodeo I, Gulden S, Amelio GS, Cortesi V, Manzoni F, Cervellini G, Cerasani J, Menis C, Pesenti N, Tripodi M, Santi L, Maggioni M, Lonati C, Oldoni S, Algieri F, Garrido F, Bernardo ME, Mosca F, Cavallaro G. Human Bone Marrow-Derived Mesenchymal Stromal Cells Reduce the Severity of Experimental Necrotizing Enterocolitis in a Concentration-Dependent Manner. Cells 2023; 12:cells12050760. [PMID: 36899900 PMCID: PMC10000931 DOI: 10.3390/cells12050760] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/10/2023] [Accepted: 02/24/2023] [Indexed: 03/06/2023] Open
Abstract
Necrotizing enterocolitis (NEC) is a devastating gut disease in preterm neonates. In NEC animal models, mesenchymal stromal cells (MSCs) administration has reduced the incidence and severity of NEC. We developed and characterized a novel mouse model of NEC to evaluate the effect of human bone marrow-derived MSCs (hBM-MSCs) in tissue regeneration and epithelial gut repair. NEC was induced in C57BL/6 mouse pups at postnatal days (PND) 3-6 by (A) gavage feeding term infant formula, (B) hypoxia/hypothermia, and (C) lipopolysaccharide. Intraperitoneal injections of PBS or two hBM-MSCs doses (0.5 × 106 or 1 × 106) were given on PND2. At PND 6, we harvested intestine samples from all groups. The NEC group showed an incidence of NEC of 50% compared with controls (p < 0.001). Severity of bowel damage was reduced by hBM-MSCs compared to the PBS-treated NEC group in a concentration-dependent manner, with hBM-MSCs (1 × 106) inducing a NEC incidence reduction of up to 0% (p < 0.001). We showed that hBM-MSCs enhanced intestinal cell survival, preserving intestinal barrier integrity and decreasing mucosal inflammation and apoptosis. In conclusion, we established a novel NEC animal model and demonstrated that hBM-MSCs administration reduced the NEC incidence and severity in a concentration-dependent manner, enhancing intestinal barrier integrity.
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Affiliation(s)
- Livia Provitera
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Andrea Tomaselli
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Genny Raffaeli
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
- Correspondence: (G.R.); (G.C.); Tel.: +39-(02)-55032234 (G.C.); Fax: +39-(02)-55032217 (G.R. & G.C.)
| | - Stefania Crippa
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Cristina Arribas
- Department of Pediatrics, Clínica Universidad de Navarra, 28027 Madrid, Spain
| | - Ilaria Amodeo
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Silvia Gulden
- Neonatal Intensive Care Unit, Sant’Anna Hospital, 22042 Como, Italy
| | - Giacomo Simeone Amelio
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Valeria Cortesi
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Francesca Manzoni
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Gaia Cervellini
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Jacopo Cerasani
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Camilla Menis
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Nicola Pesenti
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Statistics and Quantitative Methods, Division of Biostatistics, Epidemiology and Public Health, University of Milano-Bicocca, 20126 Milan, Italy
- Revelo Datalabs S.R.L., 20142 Milan, Italy
| | - Matteo Tripodi
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Ludovica Santi
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Marco Maggioni
- Department of Pathology, Fondazione Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Caterina Lonati
- Center for Preclinical Investigation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Samanta Oldoni
- Center for Preclinical Investigation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Francesca Algieri
- Research and Development Unit, Postbiotica S.R.L., 20123 Milan, Italy
| | - Felipe Garrido
- Department of Pediatrics, Clínica Universidad de Navarra, 28027 Madrid, Spain
| | - Maria Ester Bernardo
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Pediatric Immunohematology Unit, BMT Program, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Maternal and Child Department, Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Fabio Mosca
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Giacomo Cavallaro
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Correspondence: (G.R.); (G.C.); Tel.: +39-(02)-55032234 (G.C.); Fax: +39-(02)-55032217 (G.R. & G.C.)
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Manohar K, Mesfin FM, Liu J, Shelley WC, Brokaw JP, Markel TA. Gut-Brain cross talk: The pathogenesis of neurodevelopmental impairment in necrotizing enterocolitis. Front Pediatr 2023; 11:1104682. [PMID: 36873645 PMCID: PMC9975605 DOI: 10.3389/fped.2023.1104682] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 01/23/2023] [Indexed: 02/17/2023] Open
Abstract
Necrotizing enterocolitis (NEC) is a devastating condition of multi-factorial origin that affects the intestine of premature infants and results in high morbidity and mortality. Infants that survive contend with several long-term sequelae including neurodevelopmental impairment (NDI)-which encompasses cognitive and psychosocial deficits as well as motor, vision, and hearing impairment. Alterations in the gut-brain axis (GBA) homeostasis have been implicated in the pathogenesis of NEC and the development of NDI. The crosstalk along the GBA suggests that microbial dysbiosis and subsequent bowel injury can initiate systemic inflammation which is followed by pathogenic signaling cascades with multiple pathways that ultimately lead to the brain. These signals reach the brain and activate an inflammatory cascade in the brain resulting in white matter injury, impaired myelination, delayed head growth, and eventual downstream NDI. The purpose of this review is to summarize the NDI seen in NEC, discuss what is known about the GBA, explore the relationship between the GBA and perinatal brain injury in the setting of NEC, and finally, highlight the existing research into possible therapies to help prevent these deleterious outcomes.
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Affiliation(s)
- Krishna Manohar
- Department of Surgery, Indiana University School of Medicine (IUSM), Indianapolis, IN, United States
| | - Fikir M Mesfin
- Department of Surgery, Indiana University School of Medicine (IUSM), Indianapolis, IN, United States
| | - Jianyun Liu
- Department of Surgery, Indiana University School of Medicine (IUSM), Indianapolis, IN, United States
| | - W Christopher Shelley
- Department of Surgery, Indiana University School of Medicine (IUSM), Indianapolis, IN, United States
| | - John P Brokaw
- Department of Surgery, Indiana University School of Medicine (IUSM), Indianapolis, IN, United States
| | - Troy A Markel
- Department of Surgery, Indiana University School of Medicine (IUSM), Indianapolis, IN, United States.,Riley Hospital for Children, Indiana University Health, Indianapolis, IN, United States
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Wellmann S. Stem-cell therapy in neonates - an option? J Perinat Med 2022:jpm-2022-0507. [PMID: 36480466 DOI: 10.1515/jpm-2022-0507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 11/16/2022] [Indexed: 12/13/2022]
Abstract
Within the fast-growing field of regenerative medicine stem-cell therapy is well established in various hematologic and immunologic diseases and has received a recent substantial boost from the introduction of gene editing and gene transfer technologies. In neonates, for example, regenerative medicine may benefit those with congenital or acquired disease due to prematurity or perinatal hypoxia-ischemia. We compare and contrast the two main approaches - autologous vs. allogeneic - and summarize the recent advances and applications of interventional stem-cell research in perinatally acquired disorders such as intraventricular hemorrhage, hypoxia-ischemia and stroke. After discussing stem-cell sources and routes of administration, we conclude by highlighting the key opportunities and obstacles in this exciting field.
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Affiliation(s)
- Sven Wellmann
- Department of Neonatology, University Children's Hospital Regensburg (KUNO), Hospital St. Hedwig of the Order of St. John, University of Regensburg, Regensburg, Germany
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14
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Delavogia E, Ntentakis DP, Cortinas JA, Fernandez-Gonzalez A, Alex Mitsialis S, Kourembanas S. Mesenchymal Stromal/Stem Cell Extracellular Vesicles and Perinatal Injury: One Formula for Many Diseases. Stem Cells 2022; 40:991-1007. [PMID: 36044737 PMCID: PMC9707037 DOI: 10.1093/stmcls/sxac062] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/05/2022] [Indexed: 11/12/2022]
Abstract
Over the past decades, substantial advances in neonatal medical care have increased the survival of extremely premature infants. However, there continues to be significant morbidity associated with preterm birth with common complications including bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), neuronal injury such as intraventricular hemorrhage (IVH) or hypoxic ischemic encephalopathy (HIE), as well as retinopathy of prematurity (ROP). Common developmental immune and inflammatory pathways underlie the pathophysiology of such complications providing the opportunity for multisystem therapeutic approaches. To date, no single therapy has proven to be effective enough to prevent or treat the sequelae of prematurity. In the past decade mesenchymal stem/stromal cell (MSC)-based therapeutic approaches have shown promising results in numerous experimental models of neonatal diseases. It is now accepted that the therapeutic potential of MSCs is comprised of their secretome, and several studies have recognized the small extracellular vesicles (sEVs) as the paracrine vector. Herein, we review the current literature on the MSC-EVs as potential therapeutic agents in neonatal diseases and comment on the progress and challenges of their translation to the clinical setting.
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Affiliation(s)
- Eleni Delavogia
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Dimitrios P Ntentakis
- Retina Service, Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - John A Cortinas
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Angeles Fernandez-Gonzalez
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - S Alex Mitsialis
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Stella Kourembanas
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
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15
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Comparison and Investigation of Exosomes from Human Amniotic Fluid Stem Cells and Human Breast Milk in Alleviating Neonatal Necrotizing Enterocolitis. Stem Cell Rev Rep 2022; 19:754-766. [PMID: 36385400 PMCID: PMC10070207 DOI: 10.1007/s12015-022-10470-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/18/2022] [Indexed: 11/17/2022]
Abstract
Abstract
In view of the devastating impact of neonatal necrotizing enterocolitis (NEC) on newborns, the research on its intervention is particularly important. Although exosomes from human amniotic fluid stem cells (AFSC) and human breast milk (HBM) can protect against NEC, their mechanisms remain unclear. Here, we intend to compare the intervention effects of two types of exosomes on NEC mouse model and reveal their respective regulatory mechanisms. In general, both AFSC-derived exosomes (AFSC-exos) and HBM-derived exosomes (HBM- exos) can alleviate NEC- associated intestinal injury, significantly reduce NEC score, and reduce systemic and ileal inflammation and NEC related brain injury during experimental NEC. However, the mode and mechanism of action of the two sources of exosomes were not identical. In vivo, the number of ileal crypts was more significantly restored after HBM-exos intervention than AFSC-exos, and in vitro, HBM-exos preferentially inhibited the inflammatory response of intestinal epithelial cells (IECs), whereas AFSC-exos preferentially regulated the migration of IECs. Mechanistically, GO and KEGG analyses revealed the different therapeutic mechanisms of AFSC-exos and HBM-exos in NEC. Taken together, our results illustrate that AFSC-exos and HBM-exos reduce the severity of experimental NEC and intestinal damage through different mechanisms, supporting the potential of cell-free or breast milk free exosome therapy for NEC.
Graphical Abstract
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16
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Devyaltovskaya MG, Nikitchanko DY, Potapnev MP, Petyovka NV, Kastsiunina VS. The First Experience of Application the Umbilical Cord-Derived Human Autologous Mesenchymal Stromal Cells for the Rehabilitation Therapy of Premature Infants with Extremely Low Body Weight and Hypoxic-Ischemic Encephalopathy. Bull Exp Biol Med 2022; 174:142-146. [PMID: 36437330 DOI: 10.1007/s10517-022-05663-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Indexed: 11/29/2022]
Abstract
Two clinical cases of the use of cell therapy with umbilical cord-derived autologous mesenchymal stromal cells in the rehabilitation therapy of extremely premature newborns (27-28 weeks gestation, body weights 900 and 870 g, respectively) with hypoxic-ischemic encephalopathy are described. The girls were born by caesarean section; the 1-min Apgar score was 6 points. After resuscitation including artificial ventilation, stabilization of the condition was achieved against the background of the development of hypoxic-ischemic encephalopathy. Rehabilitation therapy included administration of umbilical cord-derived mesenchymal stromal cells harvested at birth. The cells were injected in a dose of 1.6-7 million/kg body weight at the age of 3, 6, 12 months (the first patient) and 3, 6, 9, 15 months (the second patient). Psychoneurological developmental delay was scored using the Hellbrügge scale. Cell therapy induced no significant adverse reactions and improved the psychomotor development of children.
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Affiliation(s)
- M G Devyaltovskaya
- Republican Scientific and Practical Center "Mother and Child", Minsk, Belarus
| | - D Yu Nikitchanko
- Republican Scientific and Practical Center "Mother and Child", Minsk, Belarus
| | - M P Potapnev
- Republican Center for Transfusiology and Medical Biotechnologies, Minsk, Belarus.
| | - N V Petyovka
- Republican Center for Transfusiology and Medical Biotechnologies, Minsk, Belarus
| | - V S Kastsiunina
- Republican Center for Transfusiology and Medical Biotechnologies, Minsk, Belarus
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17
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Di SJ, Wu SY, Liu TJ, Shi YY. Stem cell therapy as a promising strategy in necrotizing enterocolitis. Mol Med 2022; 28:107. [PMID: 36068527 PMCID: PMC9450300 DOI: 10.1186/s10020-022-00536-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/29/2022] [Indexed: 11/10/2022] Open
Abstract
Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease that affects newborns, particularly preterm infants, and is associated with high morbidity and mortality. No effective therapeutic strategies to decrease the incidence and severity of NEC have been developed to date. Stem cell therapy has been explored and even applied in various diseases, including gastrointestinal disorders. Animal studies on stem cell therapy have made great progress, and the anti-inflammatory, anti-apoptotic, and intestinal barrier enhancing effects of stem cells may be protective against NEC clinically. In this review, we discuss the therapeutic mechanisms through which stem cells may function in the treatment of NEC.
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Affiliation(s)
- Si-Jia Di
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Si-Yuan Wu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Tian-Jing Liu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Yong-Yan Shi
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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Bench to bedside - new insights into the pathogenesis of necrotizing enterocolitis. Nat Rev Gastroenterol Hepatol 2022; 19:468-479. [PMID: 35347256 DOI: 10.1038/s41575-022-00594-x] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/22/2022] [Indexed: 12/12/2022]
Abstract
Necrotizing enterocolitis (NEC) is the leading cause of death and disability from gastrointestinal disease in premature infants. Recent discoveries have shed light on a unifying theorem to explain the pathogenesis of NEC, suggesting that specific treatments might finally be forthcoming. A variety of experiments have highlighted how the interaction between bacterial signalling receptors on the premature intestine and an abnormal gut microbiota incites a pro-inflammatory response in the intestinal mucosa and its underlying endothelium that leads to NEC. Central amongst the bacterial signalling receptors implicated in NEC development is the lipopolysaccharide receptor Toll-like receptor 4 (TLR4), which is expressed at higher levels in the premature gut than in the full-term gut. The high prenatal intestinal expression of TLR4 reflects the role of TLR4 in the regulation of normal gut development, and supports additional studies indicating that NEC develops in response to signalling events that occur in utero. This Review provides new evidence explaining the pathogenesis of NEC, explores new findings indicating that NEC development has origins before birth, and discusses future questions and opportunities for discovery in this field.
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Chaubey S, Bhandari V. Stem cells in neonatal diseases: An overview. Semin Fetal Neonatal Med 2022; 27:101325. [PMID: 35367186 DOI: 10.1016/j.siny.2022.101325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Preterm birth and its common complications are major causes of infant mortality and long-term morbidity. Despite great advances in understanding the pathogenesis of neonatal diseases and improvements in neonatal intensive care, effective therapies for the prevention or treatment for these conditions are still lacking. Stem cell (SC) therapy is rapidly emerging as a novel therapeutic tool for several diseases of the newborn with encouraging pre-clinical results that hold promise for translation to the bedside. The utility of different types of SCs in neonatal diseases is being explored. SC therapeutic efficacy is closely associated with its secretome-conditioned media and SC-derived extracellular vesicles, and a subsequent paracrine action in response to tissue injuries. In the current review, we summarize the pre-clinical and clinical studies of SCs and its secretome in diverse preterm and term birth-related diseases, thereby providing new insights for future therapies in neonatal medicine.
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Affiliation(s)
- Sushma Chaubey
- Department of Biomedical Engineering, Widener University, Chester, PA, 19013, USA.
| | - Vineet Bhandari
- Neonatology Research Laboratory, Department of Pediatrics, The Children's Regional Hospital at Cooper, Cooper Medical School of Rowan University, Suite Dorrance 755, One Cooper Plaza, Camden, NJ, 08103, USA.
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20
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Damianos A, Xu K, Kalin GT, Kalinichenko VV. Placental tissue stem cells and their role in neonatal diseases. Semin Fetal Neonatal Med 2022; 27:101322. [PMID: 34953760 DOI: 10.1016/j.siny.2021.101322] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Neonatal diseases such as hypoxic ischemic encephalopathy, diseases of prematurity and congenital disorders carry increased morbidity and mortality. Despite technological advancements, their incidence remains largely unabated. Stem cell (SC) interventions are novel therapies in the neonatal world. In pre-clinical models of neonatal diseases, SC applications have shown encouraging results. SC sources vary, with the bone marrow being the most utilized. However, the ability to harvest bone marrow SCs from neonates is limited. Placental-tissue derived SCs (PTSCs), provide an alternative and highly attractive source. Human placentas, the cornerstone of fetal survival, are abundant with such cells. Comparing to adult pools, PTSCs exhibit increased potency, decreased immunogenicity and stronger anti-inflammatory effects. Several types of PTSCs have been identified, with mesenchymal stem cells being the most utilized population. This review will focus on PTSCs and their pre-clinical and clinical applications in neonatology.
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Affiliation(s)
- Andreas Damianos
- Division of Neonatology and Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
| | - Kui Xu
- Center for Lung Regenerative Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Gregory T Kalin
- Center for Lung Regenerative Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Vladimir V Kalinichenko
- Division of Neonatology and Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Center for Lung Regenerative Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
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Shu J, Jiang L, Wang M, Wang R, Wang X, Gao C, Xia Z. Human bone marrow mesenchymal stem cells-derived exosomes protect against nerve injury via regulating immune microenvironment in neonatal hypoxic-ischemic brain damage model. Immunobiology 2022; 227:152178. [DOI: 10.1016/j.imbio.2022.152178] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 12/14/2021] [Accepted: 01/05/2022] [Indexed: 02/08/2023]
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22
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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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Zhuxiao R, Ruoyu H, Liling Y, Xuejun R, Chunhui Y, Wanfen R, Zhifeng C, Yiheng D, Qi Z, Wei W, Zhipeng L, Jingjun P, Qigai Y, Jie Y. Autologous cord blood mononuclear cell infusion for the prevention of bronchopulmonary dysplasia in very preterm monozygotic twins: A study protocol for a randomized, placebo-controlled, double-blinded multicenter trial. Front Pediatr 2022; 10:884366. [PMID: 36568414 PMCID: PMC9780444 DOI: 10.3389/fped.2022.884366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 11/15/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Preterm-associated complications remain the main cause of neonatal death. Survivors face the challenges of short- and long-term complications. Among all complications, bronchopulmonary dysplasia (BPD) remains the first important cause of neonatal mortality and morbidity. Current treatment does not address this main preterm complication. Cord blood is regarded as a convenient source of stem cells. The paracrine bioactive factors of stem cells contribute to tissue repair and immune modulation. Our clinical studies and those of others have shown that cord blood cell infusion is both safe and possibly effective in the prevention and treatment of BPD. The therapeutic use of cord blood has emerged as a promising therapy. However, the genetic heterogeneity between control and intervention groups may reduce the comparability especially among small sample trials. The purpose of this study protocol is to investigate the effects of autologous cord blood mononuclear cell (ACBMNC) infusion on the prevention of BPD in very preterm monozygotic twins of less than 32 gestation weeks. METHODS In this prospective, randomized, placebo-controlled, double-blinded multicenter clinical trial, 60 pairs of monozygotic twin preterm neonates of less than 32 weeks admitted to the Neonatal Intensive Care Unit are randomly assigned to receive intravenous ACBMNC infusion (targeted at 5 × 107 cells/kg) or placebo (normal saline) within 24 h after birth in a 1:1 ratio. The primary outcome will be survival without BPD at 36 weeks of postmenstrual age. The secondary outcomes will include the mortality rate, BPD severity, other common preterm complication rates, respiratory support duration, length and cost of hospitalization, and long-term respiratory and neurodevelopmental outcomes during a 2-year follow-up. Furthermore, we will perform single-cell RNA sequencing for cord blood cells and blood cells 3-10 days after intervention and detect whether reactive oxygen species and inflammatory cytokines are present. CONCLUSION This will be the first randomized, placebo-controlled, double-blinded trial to evaluate the efficacy of ACBMNC infusion to prevent BPD in monozygotic twin premature infants and investigate the underlying protective mechanisms. The results of this trial will provide valuable clinical evidence for translational application of cord blood cell therapy in very preterm infants.Trial registration: ClinicalTrials.gov, NCT05087498, registered 10/09/2021, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000BAD7&selectaction=Edit&uid=U0002PLA&ts=2&cx=qvyylv.
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Affiliation(s)
- Ren Zhuxiao
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, China
| | - Huang Ruoyu
- Department of Neonatology, The First Affiliated Hospital of Kangda College of Nanjing Medical University, Nanjing, China
| | - Yang Liling
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, China
| | - Ren Xuejun
- Department of Neonatology, Dongguan Maternal & Child Health Hospital, Dongguan, China
| | - Yang Chunhui
- Department of Neonatology, Zhongshan Boai Hospital, Zhongshan, China
| | - Ruan Wanfen
- Department of Neonatology, Shunde Hospital, Southern Medical University, Foshan, China
| | - Chen Zhifeng
- Department of Neonatology, Dongguan Hospital, Southern Medical University, Dongguan, China
| | - Dai Yiheng
- Department of Neonatology, Affiliated Maternal & Child Health Hospital of Foshan, South Medical University, Foshan, China
| | - Zhang Qi
- Department of Clinic Genetic Center, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, China
| | - Wei Wei
- Guangdong Cord Blood Bank/Guangzhou Municipality Tianhe Nuoya Bio-Engineering Co. Ltd, Guangzhou, China
| | - Liu Zhipeng
- Guangdong Cord Blood Bank/Guangzhou Municipality Tianhe Nuoya Bio-Engineering Co. Ltd, Guangzhou, China
| | - Pei Jingjun
- Department of Neonatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yin Qigai
- Department of Neonatology, The First Affiliated Hospital of Kangda College of Nanjing Medical University, Nanjing, China
| | - Yang Jie
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, China.,Department of Neonatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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24
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Potapnev MP. Analysis of approaches to increase the efficacy of cell therapy based on mesenchymal stromal cells. GENES & CELLS 2021; 16:22-28. [DOI: 10.23868/202112003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The review considers the main stages of isolating, processing and clinical use of human mesenchymal stromal cells (MSCs). They included: donor selection, selection of the source of MSCs, methods of isolation of cellular suspension from tissue, culturing in vitro for cell biomass propagation, priming of the resulting cell product, timing and ways of its clinical application, selection of the recipient of MSCs. The analysis of the stages of MSCs preparation and conditions for their use was carried out from the position of the influence on the final therapeutic effect of cell therapy in patients (or experimental animals - in preclinical studies). The optimal parameters of work with MSCs at each stage, the possibility to improve their quality / biological activity in order to increase their therapeutic efficacy were determined. The analysis and ways of avoiding the influence of adverse factors associated with the manufacturing and use of MSCs on the effectiveness of cell therapy in patients were given.
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25
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Salimi U, Dummula K, Tucker MH, Dela Cruz CS, Sampath V. Postnatal Sepsis and Bronchopulmonary Dysplasia in Premature Infants: Mechanistic Insights into "New BPD". Am J Respir Cell Mol Biol 2021; 66:137-145. [PMID: 34644520 DOI: 10.1165/rcmb.2021-0353ps] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Bronchopulmonary dysplasia (BPD) is a debilitating disease in premature infants resulting from lung injury that disrupts alveolar and pulmonary vascular development. Despite the use of lung-protective ventilation and targeted oxygen therapy, BPD rates have not significantly changed over the last decade. Recent evidence suggests that sepsis and conditions initiating the systemic inflammatory response syndrome in preterm infants are key risk factors for BPD. However, the mechanisms by which sepsis-associated systemic inflammation and microbial dissemination program aberrant lung development are not fully understood. Progress has been made within the last 5 years with the inception of animal models allowing mechanistic investigations into neonatal acute lung injury and alveolar remodeling due to endotoxemia and NEC. These recent studies begin to unravel the pathophysiology of early endothelial immune activation via pattern recognition receptors such as Toll Like Receptor 4 and disruption of critical lung developmental processes such as angiogenesis, extracellular matrix deposition, and ultimately alveologenesis. Here we review scientific evidence from preclinical models of neonatal sepsis-induced lung injury to new data emerging from clinical literature.
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Affiliation(s)
- Umar Salimi
- Yale University, 5755, Pediatrics, New Haven, Connecticut, United States
| | - Krishna Dummula
- Children's Mercy, 4204, Pediatrics, Kansas City, Missouri, United States
| | - Megan H Tucker
- Children's Mercy, 4204, Pediatrics, Kansas City, Missouri, United States
| | - Charles S Dela Cruz
- Yale University, Pulmonary and Critical Care Medicine, New Haven, Connecticut, United States
| | - Venkatesh Sampath
- Children\'s Mercy Hospitals and Clinics, 4204, Pediatrics, Kansas City, Missouri, United States;
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Pan HX, Zhang CS, Lin CH, Chen MM, Zhang XZ, Yu N. Mucin 1 and interleukin-11 protein expression and inflammatory reactions in the intestinal mucosa of necrotizing enterocolitis children after surgery. World J Clin Cases 2021; 9:7372-7380. [PMID: 34616804 PMCID: PMC8464442 DOI: 10.12998/wjcc.v9.i25.7372] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/30/2021] [Accepted: 07/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Necrotizing enterocolitis (NEC) of the newborn is a frequently occurring clinical disease in infants. The mortality rate of NEC in premature infants is as high as 50%, and the morbidity rate is on the rise. NEC has already caused serious impacts on newborn survival and poses serious threats to both children and families.
AIM To investigate the expression and significance of mucin 1 (MUC1) and interleukin-11 (IL-11) in the intestinal mucosa of infants with neonatal NEC after surgery.
METHODS Forty-eight postoperative intestinal mucosal specimens from children with NEC (NEC group) and twenty-two intestinal mucosal specimens from children with congenital intestinal atresia (control group) were collected in our hospital. Immunohistochemical staining and Western blot analysis were used to examine the protein expression of MUC-1 and IL-11 in the two groups. The serum levels of tumor necrosis factor-α (TNF-α) and IL-1β in the two groups were measured by enzyme-linked immunosorbent assay, and the relationship between MUC-1 and IL-11 protein expression and serum TNF-α and IL-1β levels was analyzed by the linear correlation method.
RESULTS The protein expression of MUC-1 and IL-11 in the NEC group was significantly lower than that in the control group, and the difference was statistically significant (P < 0.05). The levels of serum TNF-α and IL-1β in the NEC group were significantly higher than those in the control group (P < 0.05). The protein expression of MUC-1 and IL-11 in the NEC group negatively correlated with serum TNF-α and IL-1β levels (P < 0.05). There was a significant negative correlation between the protein expression of MUC-1 and IL-11 and the levels of serum TNF-α and IL-1β in the NEC group.
CONCLUSION The protein expression of MUC1 and IL-11 in the intestinal mucosa of children with NEC is significantly downregulated after surgery. This downregulation may be involved in the pathogenesis of this disease and has a certain correlation with inflammatory response factors in children with NEC.
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Affiliation(s)
- Hong-Xia Pan
- Department of Clinical Laboratory Medicine, Suzhou BenQ Medical Center, Affiliated BenQ Hospital of Nanjing Medical University, Suzhou 215011, Jiangsu Province, China
| | - Chang-Song Zhang
- Department of Clinical Laboratory Medicine, The Affiliated Suzhou Science and Technology Town Hospital, Nanjing Medical University, Suzhou 215153, Jiangsu Province, China
| | - Chia-Hui Lin
- General Manager's Office, Suzhou Gallant Biotech Biotechnology Co. Ltd, Suzhou 215163, Jiangsu Province, China
| | - Min-Min Chen
- Department of Clinical Laboratory Medicine, Suzhou BenQ Medical Center, Affiliated BenQ Hospital of Nanjing Medical University, Suzhou 215011, Jiangsu Province, China
| | - Xiao-Zhong Zhang
- Department of Cardiology, National High Tech Development Zone Hospital, Suzhou 215129, Jiangsu Province, China
| | - Nong Yu
- Department of Laboratory Medicine, National High Tech Development Zone Hospital, Suzhou 215129, Jiangsu Province, China
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Imaging Tolerance Induction in Neonatal Mice: Hierarchical Interplay Between Allogeneic Adult and Neonatal Immune Cells. Transplantation 2021; 105:1730-1746. [PMID: 33273316 DOI: 10.1097/tp.0000000000003566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND In Medawar's murine neonatal tolerance model, injection of adult semiallogeneic lymphohematopoietic cells (spleen cells [SC] and bone marrow cells [BMC]) tolerizes the neonatal immune system. An eventual clinical application would require fully allogeneic (allo) cells, yet little is known about the complex in vivo/in situ interplay between those cells and the nonconditioned neonatal immune system. METHODS To this end, labeled adult SC and BMC were injected into allogeneic neonates; interactions between donor and host cells were analyzed and modulated by systematic depletion/inactivation of specific donor and host immune effector cell types. RESULTS Consistent with effector cell compositions, allo-SC and allo-SC/BMC each induced lethal acute graft-versus-host disease, whereas allo-BMC alone did so infrequently. CD8 T cells from SC inoculum appeared naïve, while those of BMC were more memory-like. Age-dependent, cell-type dominance defined the interplay between adult donor cells and the neonatal host immune system such that if the dominant adult effector type was removed, then the equivalent neonatal one became dominant. Depletion of donor/host peripheral T cells protected against acute graft-versus-host disease and prolonged heart allograft survival; peripheral CD8 T-cell depletion together with CD4 T cell-costimulation blockade induced more robust tolerance. CONCLUSIONS This comprehensive study provides direct observation of the cellular interplay between allogeneic donor and host immune systems, adds to our previous work with semiallogeneic donor cells, and provides important insights for robust tolerance induction. Induction of transplant tolerance in neonates will likely require "crowd sourcing" of multiple tolerizing cell types and involve depletion of immune effector cells with costimulation blockade.
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28
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Valiulienė G, Zentelytė A, Beržanskytė E, Navakauskienė R. Metabolic Profile and Neurogenic Potential of Human Amniotic Fluid Stem Cells From Normal vs. Fetus-Affected Gestations. Front Cell Dev Biol 2021; 9:700634. [PMID: 34336852 PMCID: PMC8322743 DOI: 10.3389/fcell.2021.700634] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 06/21/2021] [Indexed: 12/04/2022] Open
Abstract
Human amniotic fluid stem cells (hAFSCs) possess some characteristics with mesenchymal stem cells (MSCs) and embryonic stem cells and have a broader differentiation potential compared to MSCs derived from other sources. Although hAFSCs are widely researched, their analysis mainly involves stem cells (SCs) obtained from normal, fetus-unaffected gestations. However, in clinical settings, knowledge about hAFSCs from normal gestations could be poorly translational, as hAFSCs from healthy and fetus-diseased gestations may differ in their differentiation and metabolic potential. Therefore, a more thorough investigation of hAFSCs derived from pathological gestations would provide researchers with the knowledge about the general characteristics of these cells that could be valuable for further scientific investigations and possible future clinical applicability. The goal of this study was to look into the neurogenic and metabolic potential of hAFSCs derived from diseased fetuses, when gestations were concomitant with polyhydramnios and compare them to hAFSCs derived from normal fetuses. Results demonstrated that these cells are similar in gene expression levels of stemness markers (SOX2, NANOG, LIN28A, etc.). However, they differ in expression of CD13, CD73, CD90, and CD105, as flow cytometry analysis revealed higher expression in hAFSCs from unaffected gestations. Furthermore, hAFSCs from “Normal” and “Pathology” groups were different in oxidative phosphorylation rate, as well as level of ATP and reactive oxygen species production. Although the secretion of neurotrophic factors BDNF and VEGF was of comparable degree, as evaluated with enzyme-linked immunosorbent assay (ELISA) test, hAFSCs from normal gestations were found to be more prone to neurogenic differentiation, compared to hAFSCs from polyhydramnios. Furthermore, hAFSCs from polyhydramnios were distinguished by higher secretion of pro-inflammatory cytokine TNFα, which was significantly downregulated in differentiated cells. Overall, these observations show that hAFSCs from pathological gestations with polyhydramnios differ in metabolic and inflammatory status and also possess lower neurogenic potential compared to hAFSCs from normal gestations. Therefore, further in vitro and in vivo studies are necessary to dissect the potential of hAFSCs from polyhydramnios in stem cell-based therapies. Future studies should also search for strategies that could improve the characteristics of hAFSCs derived from diseased fetuses in order for those cells to be successfully applied for regenerative medicine purposes.
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Affiliation(s)
- Giedrė Valiulienė
- Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Aistė Zentelytė
- Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Elizabet Beržanskytė
- Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Rūta Navakauskienė
- Department of Molecular Cell Biology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania
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29
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Robertson NJ, Meehan C, Martinello KA, Avdic-Belltheus A, Boggini T, Mutshiya T, Lingam I, Yang Q, Sokolska M, Charalambous X, Bainbridge A, Hristova M, Kramer BW, Golay X, Weil B, Lowdell MW. Human umbilical cord mesenchymal stromal cells as an adjunct therapy with therapeutic hypothermia in a piglet model of perinatal asphyxia. Cytotherapy 2021; 23:521-535. [PMID: 33262073 PMCID: PMC8139415 DOI: 10.1016/j.jcyt.2020.10.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 10/12/2020] [Accepted: 10/30/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND With therapeutic hypothermia (HT) for neonatal encephalopathy, disability rates are reduced, but not all babies benefit. Pre-clinical rodent studies suggest mesenchymal stromal cells (MSCs) augment HT protection. AIMS The authors studied the efficacy of intravenous (IV) or intranasal (IN) human umbilical cord-derived MSCs (huMSCs) as adjunct therapy to HT in a piglet model. METHODS A total of 17 newborn piglets underwent transient cerebral hypoxia-ischemia (HI) and were then randomized to (i) HT at 33.5°C 1-13 h after HI (n = 7), (ii) HT+IV huMSCs (30 × 106 cells) at 24 h and 48 h after HI (n = 5) or (iii) HT+IN huMSCs (30 × 106 cells) at 24 h and 48 h after HI (n = 5). Phosphorus-31 and hydrogen-1 magnetic resonance spectroscopy (MRS) was performed at 30 h and 72 h and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and oligodendrocytes quantified. In two further piglets, 30 × 106 IN PKH-labeled huMSCs were administered. RESULTS HI severity was similar between groups. Amplitude-integrated electroencephalogram (aEEG) recovery was more rapid for HT+IN huMSCs compared with HT from 25 h to 42 h and 49 h to 54 h (P ≤ 0.05). MRS phosphocreatine/inorganic phosphate was higher on day 2 in HT+IN huMSCs than HT (P = 0.035). Comparing HT+IN huMSCs with HT and HT+IV huMSCs, there were increased OLIG2 counts in hippocampus (P = 0.011 and 0.018, respectively), internal capsule (P = 0.013 and 0.037, respectively) and periventricular white matter (P = 0.15 for IN versus IV huMSCs). Reduced TUNEL-positive cells were seen in internal capsule with HT+IN huMSCs versus HT (P = 0.05). PKH-labeled huMSCs were detected in the brain 12 h after IN administration. CONCLUSIONS After global HI, compared with HT alone, the authors saw beneficial effects of HT+IN huMSCs administered at 24 h and 48 h (30 × 106 cells/kg total dose) based on more rapid aEEG recovery, improved 31P MRS brain energy metabolism and increased oligodendrocyte survival at 72 h.
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Affiliation(s)
| | | | | | | | - Tiziana Boggini
- Institute for Women's Health, University College London, London, UK
| | - Tatenda Mutshiya
- Institute for Women's Health, University College London, London, UK
| | - Ingran Lingam
- Institute for Women's Health, University College London, London, UK
| | - Qin Yang
- Institute for Women's Health, University College London, London, UK
| | | | | | - Alan Bainbridge
- University College London Hospitals NHS Foundation Trust, London, UK
| | - Mariya Hristova
- Institute for Women's Health, University College London, London, UK
| | - Boris W Kramer
- Department of Pediatrics, University of Maastricht, Maastricht, the Netherlands
| | - Xavier Golay
- Institute for Women's Health, University College London, London, UK
| | - Ben Weil
- Royal Free London NHS Foundation Trust, London, UK
| | - Mark W Lowdell
- Institute for Women's Health, University College London, London, UK; Royal Free London NHS Foundation Trust, London, UK
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Abstract
Necrotizing enterocolitis (NEC) is an inflammatory disease affecting premature infants. Intestinal microbial composition may play a key role in determining which infants are predisposed to NEC and when infants are at highest risk of developing NEC. It is unclear how to optimize antibiotic therapy in preterm infants to prevent NEC and how to optimize antibiotic regimens to treat neonates with NEC. This article discusses risk factors for NEC, how dysbiosis in preterm infants plays a role in the pathogenesis of NEC, and how probiotic and antibiotic therapy may be used to prevent and/or treat NEC and its sequelae.
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Affiliation(s)
- Jennifer Duchon
- Division of Newborn Medicine, Jack and Lucy Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1000 10th Avenue, New York, NY 10019, USA
| | - Maria E Barbian
- Division of Neonatal-Perinatal Medicine, Emory University School of Medicine and Children's Healthcare of Atlanta, 2015 Uppergate Drive Northeast, 3rd Floor, Atlanta, GA 30322, USA
| | - Patricia W Denning
- Division of Neonatal-Perinatal Medicine, Emory University School of Medicine, Children's Healthcare of Atlanta, Emory University Hospital Midtown, 550 Peachtree Street, 3rd Floor MOT, Atlanta, GA 30308, USA.
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Muehlbacher T, Bassler D, Bryant MB. Evidence for the Management of Bronchopulmonary Dysplasia in Very Preterm Infants. CHILDREN (BASEL, SWITZERLAND) 2021; 8:298. [PMID: 33924638 PMCID: PMC8069828 DOI: 10.3390/children8040298] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/08/2021] [Accepted: 04/09/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Very preterm birth often results in the development of bronchopulmonary dysplasia (BPD) with an inverse correlation of gestational age and birthweight. This very preterm population is especially exposed to interventions, which affect the development of BPD. OBJECTIVE The goal of our review is to summarize the evidence on these daily procedures and provide evidence-based recommendations for the management of BPD. METHODS We conducted a systematic literature research using MEDLINE/PubMed on antenatal corticosteroids, surfactant-replacement therapy, caffeine, ventilation strategies, postnatal corticosteroids, inhaled nitric oxide, inhaled bronchodilators, macrolides, patent ductus arteriosus, fluid management, vitamin A, treatment of pulmonary hypertension and stem cell therapy. RESULTS Evidence provided by meta-analyses, systematic reviews, randomized controlled trials (RCTs) and large observational studies are summarized as a narrative review. DISCUSSION There is strong evidence for the use of antenatal corticosteroids, surfactant-replacement therapy, especially in combination with noninvasive ventilation strategies, caffeine and lung-protective ventilation strategies. A more differentiated approach has to be applied to corticosteroid treatment, the management of patent ductus arteriosus (PDA), fluid-intake and vitamin A supplementation, as well as the treatment of BPD-associated pulmonary hypertension. There is no evidence for the routine use of inhaled bronchodilators and prophylactic inhaled nitric oxide. Stem cell therapy is promising, but should be used in RCTs only.
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Affiliation(s)
- Tobias Muehlbacher
- Department of Neonatology, University Hospital Zurich, 8091 Zurich, Switzerland; (D.B.); (M.B.B.)
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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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Baker EK, Wallace EM, Davis PG, Malhotra A, Jacobs SE, Hooper SB, Lim R. A protocol for cell therapy infusion in neonates. Stem Cells Transl Med 2021; 10:773-780. [PMID: 33405397 PMCID: PMC8046110 DOI: 10.1002/sctm.20-0281] [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] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 11/05/2020] [Accepted: 11/29/2020] [Indexed: 01/22/2023] Open
Abstract
Cell therapies for neonatal morbidities are progressing to early phase clinical trials. However, protocols for intravenous (IV) delivery of cell therapies to infants have not been evaluated. It has been assumed the cell dose prescribed is the dose delivered. Early in our clinical trial of human amnion epithelial cells (hAECs), we observed cells settling in the syringe and IV tubing used to deliver the suspension. The effect on dose delivery was unknown. We aimed to quantify this observation and determine an optimal protocol for IV delivery of hAECs to extremely preterm infants. A standard pediatric infusion protocol was modeled in the laboratory. A syringe pump delivered the hAEC suspension over 60 minutes via a pediatric blood transfusion set (200‐μm filter and 2.2 mL IV line). The infusion protocol was varied by agitation methods, IV‐line volumes (0.2‐2.2 mL), albumin concentrations (2% vs 4%), and syringe orientations (horizontal vs vertical) to assess whether these variables influenced the dose delivered. The influence of flow rate (3‐15 mL/h) was assessed after other variables were optimized. The standard infusion protocol delivered 17.6% ± 9% of the intended hAEC dose. Increasing albumin concentration to 4%, positioning the syringe and IV line vertically, and decreasing IV‐line volume to 0.6 mL delivered 99.7% ± 13% of the intended hAEC dose. Flow rate did not affect dose delivery. Cell therapy infusion protocols must be considered. We describe the refinement of a cell infusion protocol that delivers intended cell doses and could form the basis of future neonatal cell delivery protocols.
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Affiliation(s)
- Elizabeth K Baker
- Newborn Research Centre, Royal Women's Hospital, Melbourne, Victoria, Australia.,Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia
| | - Euan M Wallace
- The Ritchie Centre, Hudson Institute of Medical Research, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Victoria, Australia
| | - Peter G Davis
- Newborn Research Centre, Royal Women's Hospital, Melbourne, Victoria, Australia.,Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia
| | - Atul Malhotra
- The Ritchie Centre, Hudson Institute of Medical Research, Victoria, Australia.,Department of Paediatrics, Monash University, Victoria, Australia
| | - Susan E Jacobs
- Newborn Research Centre, Royal Women's Hospital, Melbourne, Victoria, Australia.,Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Australia
| | - Stuart B Hooper
- The Ritchie Centre, Hudson Institute of Medical Research, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Victoria, Australia
| | - Rebecca Lim
- The Ritchie Centre, Hudson Institute of Medical Research, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Victoria, Australia
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Abstract
The COVID-19 pandemic has led to a major setback in both the health and economic sectors across the globe. The scale of the problem is enormous because we still do not have any specific anti-SARS-CoV-2 antiviral agent or vaccine. The human immune system has never been exposed to this novel virus, so the viral interactions with the human immune system are completely naive. New approaches are being studied at various levels, including animal in vitro models and human-based studies, to contain the COVID-19 pandemic as soon as possible. Many drugs are being tested for repurposing, but so far only remdesivir has shown some positive benefits based on preliminary reports, but these results also need further confirmation via ongoing trials. Otherwise, no other agents have shown an impactful response against COVID-19. Recently, research exploring the therapeutic application of mesenchymal stem cells (MSCs) in critically ill patients suffering from COVID-19 has gained momentum. The patients belonging to this subset are most likely beyond the point where they could benefit from an antiviral therapy because most of their illness at this stage of disease is driven by inflammatory (over)response of the immune system. In this review, we discuss the potential of MSCs as a therapeutic option for patients with COVID-19, based on the encouraging results from the preliminary data showing improved outcomes in the progression of COVID-19 disease.
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Affiliation(s)
- Kamal Kant Sahu
- Department of Hematology and Oncology, Department of Internal Medicine, Saint Vincent Hospital, Worcester, Massachusetts
| | - Ahmad Daniyal Siddiqui
- Department of Hematology and Oncology, Department of Internal Medicine, Saint Vincent Hospital, Worcester, Massachusetts
| | - Jan Cerny
- Division of Hematology and Oncology, Department of Medicine, UMass Memorial Health Care, University of Massachusetts Medical School, Worcester, Massachusetts
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35
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Frajewicki A, Laštůvka Z, Borbélyová V, Khan S, Jandová K, Janišová K, Otáhal J, Mysliveček J, Riljak V. Perinatal hypoxic-ischemic damage: review of the current treatment possibilities. Physiol Res 2020; 69:S379-S401. [PMID: 33464921 DOI: 10.33549/physiolres.934595] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Neonatal hypoxic-ischemic encephalopathy is a disorder with heterogeneous manifestation due to asphyxia during perinatal period. It affects approximately 3-12 children per 1000 live births and cause death of 1 million neonates worldwide per year. Besides, motor disabilities, seizures, impaired muscle tone and epilepsy are few of the consequences of hypoxic-ischemic encephalopathy. Despite an extensive research effort regarding various treatment strategies, therapeutic hypothermia with intensive care unit supportive treatment remains the only approved method for neonates who have suffered from moderate to severe hypoxic-ischemic encephalopathy. However, these protocols are only partially effective given that many infants still suffer from severe brain damage. Thus, further research to systematically test promising neuroprotective treatments in combination with hypothermia is essential. In this review, we discussed the pathophysiology of hypoxic-ischemic encephalopathy and delved into different promising treatment modalities, such as melatonin and erythropoietin. However, preclinical studies and clinical trials are still needed to further elucidate the mechanisms of action of these modalities.
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Affiliation(s)
- A Frajewicki
- Institute of Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
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36
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Villamor-Martinez E, Hundscheid T, Kramer BW, Hooijmans CR, Villamor E. Stem Cells as Therapy for Necrotizing Enterocolitis: A Systematic Review and Meta-Analysis of Preclinical Studies. Front Pediatr 2020; 8:578984. [PMID: 33363060 PMCID: PMC7755993 DOI: 10.3389/fped.2020.578984] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 10/13/2020] [Indexed: 12/23/2022] Open
Abstract
Background: Necrotizing enterocolitis (NEC) is the most common life-threatening gastrointestinal condition among very and extremely preterm infants. Stem cell therapy has shown some promising protective effects in animal models of intestinal injury, including NEC, but no systematic review has yet evaluated the preclinical evidence of stem cell therapy for NEC prevention or treatment. Methods: PubMed and EMBASE databases were searched for studies using an animal model of NEC with stem cells or their products. The SYRCLE tool was used for the assessment of risk of bias. A random-effects model was used to pool odds ratios (ORs) and 95% confidence interval (CI). Results: We screened 953 studies, of which nine (eight rat and one mouse models) met the inclusion criteria. All animal models induced NEC by a combination of hypothermia, hypoxia, and formula feeding. Risk of bias was evaluated as unclear on most items for all studies included. Meta-analysis found that both mesenchymal and neural stem cells and stem cell-derived exosomes reduced the incidence of all NEC (OR 0.22, 95% CI 0.16-0.32, k = 16), grade 2 NEC (OR 0.41, 95% CI 0.24-0.70, k = 16), and grade 3-4 NEC (OR 0.28, 95% CI 0.19-0.42, k = 16). k represents the number of independent effect sizes included in each meta-analysis. The effect of the exosomes was similar to that of the stem cells. Stem cells and exosomes also improved 4-day survival (OR 2.89 95% CI 2.07-4.04, k = 9) and 7-day survival (OR 3.96 95% CI 2.39-6.55, k = 5) after experimental NEC. Meta-analysis also found that stem cells reduced other indicators of intestinal injury. Conclusion: The data from this meta-analysis suggest that both stem cells and stem cell-derived exosomes prevented NEC in rodent experimental models. However, unclear risk of bias and incomplete reporting underline that poor reporting standards are common and hamper the reliable interpretation of preclinical evidence for stem cell therapy for NEC.
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Affiliation(s)
- Eduardo Villamor-Martinez
- Department of Pediatrics, Maastricht University Medical Center (MUMC+), School for Oncology and Developmental Biology (GROW), Maastricht, Netherlands
| | - Tamara Hundscheid
- Department of Pediatrics, Maastricht University Medical Center (MUMC+), School for Oncology and Developmental Biology (GROW), Maastricht, Netherlands
| | - Boris W. Kramer
- Department of Pediatrics, Maastricht University Medical Center (MUMC+), School for Oncology and Developmental Biology (GROW), Maastricht, Netherlands
| | - Carlijn R Hooijmans
- Department for Health Evidence Unit SYRCLE, Radboud University Medical Center, Nijmegen, Netherlands
| | - Eduardo Villamor
- Department of Pediatrics, Maastricht University Medical Center (MUMC+), School for Oncology and Developmental Biology (GROW), Maastricht, Netherlands
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37
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Amniotic fluid and breast milk: a rationale for breast milk stem cell therapy in neonatal diseases. Pediatr Surg Int 2020; 36:999-1007. [PMID: 32671487 DOI: 10.1007/s00383-020-04710-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/30/2020] [Indexed: 12/18/2022]
Abstract
Amniotic fluid and breast milk play important roles in structural development throughout fetal growth and infancy. Given their significance in physical maturation, many studies have investigated the therapeutic and protective roles of amniotic fluid and breast milk in neonatal diseases. Of particular interest to researchers are stem cells found in the two fluids. These stem cells have been investigated due to their ability to self-replicate, differentiate, reduce tissue damage, and their expression of pluripotent markers. While amniotic fluid stem cells have received some attention regarding their ability to treat neonatal diseases, breast milk stem cells have not been investigated to the same extent given the recency of their discovery. The purpose of this review is to compare the functions of amniotic fluid, breast milk, and their stem cells to provide a rationale for the use of breast milk stem cells as a therapy for neonatal diseases. Breast milk stem cells present as an important tool for treating neonatal diseases given their ability to reduce inflammation and tissue damage, as well as their multilineage differentiation potential, easy accessibility, and ability to be used in disease modelling.
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38
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Abstract
The 2019 Necrotizing Enterocolitis (NEC) Symposium expanded upon the NEC Society's goals of bringing stakeholders together to discuss cutting-edge science, potential therapeutics and preventative measures, as well as the patient-family perspectives of NEC. The Symposium facilitated discussions and shared knowledge with the overarching goal of creating "A World Without NEC." To accomplish this goal, new research to advance the state of the science is necessary. Over the last decade, several established investigators have significantly improved our understanding of the pathophysiology of NEC and they have paved the way for the next generation of clinician-scientists funded to perform NEC research. This article will serve to highlight the contributions of these young clinician-scientists that seek to elucidate how immune, microbial and nervous system dysregulation contributes to the pathophysiology of NEC.
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39
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Abstract
Abstract
Purpose of Review
Mesenchymal stromal cell (MSC)–based therapies provide a platform for new therapeutic strategies in lung diseases. This review provides an overview of the current status of the field, along with some of the challenges ahead including better understanding of MSC actions in different lung diseases, personalized approaches to select patients most likely to benefit, and the growing problem of stem cell tourism.
Recent Findings
A newly evolving concept suggests that MSCs shape their immunomodulatory actions depending on the environment they encounter. Furthermore, in some models, it appears that dying or dead cells may contribute to the therapeutic efficacy by activating the host response.
Summary
Despite many pre-clinical studies demonstrating that MSCs can be used to treat lung disorders, clinical trials have failed to show improved outcome. Understanding the complex interaction between MSCs and the host microenvironment is likely to be an important area for enhancing the efficacy of MSC-based cell therapies.
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40
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Soluble PTX3 of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Attenuates Hyperoxic Lung Injury by Activating Macrophage Polarization in Neonatal Rat Model. Stem Cells Int 2020; 2020:1802976. [PMID: 32399038 PMCID: PMC7204119 DOI: 10.1155/2020/1802976] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 11/18/2019] [Accepted: 11/27/2019] [Indexed: 12/13/2022] Open
Abstract
Therapeutic treatment of various inflammation-related diseases using mesenchymal stem cells (MSCs) has increased in recent years because of the paracrine action of these cells but shows several limitations. First, MSC-based therapies exhibit varying efficacies; thus, biomarkers should be determined to identify who may benefit from these candidate therapeutic agents. Second, the mechanism underlying the therapeutic effects is poorly understood. To evaluate the effects of human umbilical cord blood-derived MSCs (UCB-MSCs) on macrophages, the macrophage cell line NR8383 stimulated with lipopolysaccharide (LPS) was cocultured by UCB-MSCs. We found that UCB-MSCs mediated changes in macrophage polarization towards M2 from M1 macrophages. To identify the paracrine action underlying the anti-inflammation effect of UCB-MSCs, the secretion of UCB-MSCs exposed to LPS-stimulated NR8383 cells was tested using a biotin label-based 507 antibody array. Among the secreted proteins, we selected pentraxin-related protein PTX3/tumor necrosis factor-inducible gene 14 protein (PTX3) to investigate its association with UCB-MSCs in macrophage polarization. We found that human PTX3 was secreted from UCB-MSCs under inflammation condition and reinforced the M2 macrophage marker via the Dectin-1 receptor by activating MSK1/2 phosphorylation signaling in NR8383 cells. Accordingly, knockdown of PTX3 in UCB-MSCs significantly attenuated their therapeutic effects in a neonatal hyperoxic lung injury resulting in reduced survival, lung alveolarization, M2 marker expression, Dectin-1 levels, anti-inflammatory cytokines, and improved M1 marker expression and inflammatory cytokines compared to control MSC-injected rats. UCB-MSCs show therapeutic potential by controlling macrophage polarization. Interestingly, higher PTX3 levels in UCB-MSCs induced greater improvement in the therapeutic effects than lower PTX3 levels. Collectively, PTX3 is a potential marker with critical paracrine effects for predicting the therapeutic potential of MSC therapy in inflammatory diseases; quality control assessments using PTX3 may be useful for improving the therapeutic effects of UCB-MSCs.
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41
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Cardinali DP. An Assessment of Melatonin's Therapeutic Value in the Hypoxic-Ischemic Encephalopathy of the Newborn. Front Synaptic Neurosci 2019; 11:34. [PMID: 31920617 PMCID: PMC6914689 DOI: 10.3389/fnsyn.2019.00034] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 11/26/2019] [Indexed: 12/17/2022] Open
Abstract
Hypoxic-ischemic encephalopathy (HIE) is one of the most frequent causes of brain injury in the newborn. From a pathophysiological standpoint, a complex process takes place at the cellular and tissue level during the development of newborn brain damage in the absence of oxygen. Initially, the lesion is triggered by a deficit in the supply of oxygen to cells and tissues, causing a primary energy insufficiency. Subsequently, high energy phosphate levels recover transiently (the latent phase) that is followed by a secondary phase, in which many of the pathophysiological mechanisms involved in the development of neonatal brain damage ensue (i.e., excitotoxicity, massive influx of Ca2+, oxidative and nitrosative stress, inflammation). This leads to cell death by necrosis or apoptosis. Eventually, a tertiary phase occurs, characterized by the persistence of brain damage for months and even years after the HI insult. Hypothermia is the only therapeutic strategy against HIE that has been incorporated into neonatal intensive care units with limited success. Thus, there is an urgent need for agents with the capacity to curtail acute and chronic damage in HIE. Melatonin, a molecule of unusual phylogenetic conservation present in all known aerobic organisms, has a potential role as a neuroprotective agent both acutely and chronically in HIE. Melatonin displays a remarkable antioxidant and anti-inflammatory activity and is capable to cross the blood-brain barrier readily. Moreover, in many animal models of brain degeneration, melatonin was effective to impair chronic mechanisms of neuronal death. In animal models, and in a limited number of clinical studies, melatonin increased the level of protection developed by hypothermia in newborn asphyxia. This review article summarizes briefly the available therapeutic strategies in HIE and assesses the role of melatonin as a potentially relevant therapeutic tool to cover the hypoxia-ischemia phase and the secondary and tertiary phases following a hypoxic-ischemic insult.
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Affiliation(s)
- Daniel P. Cardinali
- Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina
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42
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Malhotra A, Lim R, Mockler JC, Wallace EM. Two-year outcomes of infants enrolled in the first-in-human study of amnion cells for bronchopulmonary dysplasia. Stem Cells Transl Med 2019; 9:289-294. [PMID: 31774236 PMCID: PMC7031636 DOI: 10.1002/sctm.19-0251] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 10/14/2019] [Accepted: 10/29/2019] [Indexed: 12/21/2022] Open
Abstract
We previously reported on the immediate safety and neonatal outcomes of six premature infants with severe bronchopulmonary dysplasia (BPD) who were administered human amnion epithelial cells (hAECs). One infant died in the neonatal period due to unrelated causes. In this study, we aimed to assess the long‐term safety and follow‐up outcomes of the five surviving infants until 2 years corrected age (CA). hAECs were administered intravenously at a dose of 1 × 106 cells per kilogram after 36 weeks postconceptional age in infants with established BPD. Study follow‐up consisted of assessment of any adverse events, growth, and respiratory, cardiac, and neurodevelopmental outcomes over four time points (6, 12, 18, and 24 months CA). Investigations included chest x‐rays, cranial and abdominal ultrasounds, and echocardiograms at regular intervals as well as a magnetic resonance imaging (MRI) brain at 2 years CA. All five infants were alive at 2 years CA. Median time to wean off oxygen was 24 (10‐36) months. Two infants had pulmonary hypertension, which resolved by 2 years of age. Four infants were rehospitalized briefly for viral or bacterial infections during the 2 years. MRI brain findings included normal (n = 1), and mild to moderate white matter loss (n = 2). Neurodisabilities diagnosed included hemiplegic cerebral palsy (n = 1), global developmental delay (n = 3), and severe hearing loss (n = 3). No evidence of tumor formation was noted on physical examinations or on any imaging. There were no long‐term adverse events observed that could be attributed to hAEC administration. We observed long‐term effects of extreme prematurity and severe BPD in the cohort.
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Affiliation(s)
- Atul Malhotra
- Monash Newborn, Monash Children's Hospital, Clayton, Victoria, Australia.,The Ritchie Centre, Hudson Institute of Medical Research, Monash University, Clayton, Victoria, Australia.,Department of Paediatrics, Monash University, Clayton, Victoria, Australia
| | - Rebecca Lim
- The Ritchie Centre, Hudson Institute of Medical Research, Monash University, Clayton, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
| | - Joanne C Mockler
- Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
| | - Euan M Wallace
- The Ritchie Centre, Hudson Institute of Medical Research, Monash University, Clayton, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
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43
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Ren Z, Xu F, Zhang X, Zhang C, Miao J, Xia X, Kang M, Wei W, Ma T, Zhang Q, Lu L, Wen J, Liu G, Liu K, Wang Q, Yang J. Autologous cord blood cell infusion in preterm neonates safely reduces respiratory support duration and potentially preterm complications. Stem Cells Transl Med 2019; 9:169-176. [PMID: 31702120 PMCID: PMC6988763 DOI: 10.1002/sctm.19-0106] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Accepted: 09/22/2019] [Indexed: 12/16/2022] Open
Abstract
Preterm birth and its complications are the leading cause of neonatal death. The main underlying pathological mechanisms for preterm complications are disruption of the normal maturation processes within the target tissues, interrupted by premature birth. Cord blood, as a new and convenient source of stem cells, may provide new, promising options for preventing preterm complications. This prospective, nonrandomized placebo controlled study aimed at investigating the effect of autologous cord blood mononuclear cells (ACBMNC) for preventing preterm associated complications. Preterm infants less than 35 weeks gestational age were assigned to receive ACBMNC (5 × 107 cells/kg) intravenous or normal saline within 8 hours after birth. Preterm complication rates were compared between two groups to demonstrate the effect of ACBMNC infusion in reducing preterm complications. Fifteen preterm infants received ACBMNC infusion, and 16 infants were assigned to the control group. There were no significant differences when comparing mortality and preterm complication rates before discharge. However, ACBMNC infusion demonstrated significant decreases in duration of mechanical ventilation (3.2 days vs 6.41 days, P = .028) and oxygen therapy (5.33 days vs 11.31 days, P = .047). ACBMNC infusion was effective in reducing respiratory support duration in very preterm infants. Due to the limited number of patients enrolled, powered randomized controlled trials are needed to better define its efficacy.
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Affiliation(s)
- Zhuxiao Ren
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Fang Xu
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Xiaoling Zhang
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Chunyi Zhang
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Jiayu Miao
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Xin Xia
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Mengmeng Kang
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Wei Wei
- Guangdong Cord Blood and Stem Cell Bank, Guangzhou, People's Republic of China
| | - Tianbao Ma
- Guangdong Cord Blood and Stem Cell Bank, Guangzhou, People's Republic of China
| | - Qi Zhang
- Department of Clinical Genetic Center, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Lijuan Lu
- Department of Obstetrics, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Jiying Wen
- Department of Obstetrics, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Guocheng Liu
- Department of Obstetrics, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Kaiyan Liu
- Institute of Hematology, People's Hospital, Peking University, Beijing, People's Republic of China
| | - Qi Wang
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China.,Guangdong Cord Blood and Stem Cell Bank, Guangzhou, People's Republic of China
| | - Jie Yang
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China
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44
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Lignelli E, Palumbo F, Myti D, Morty RE. Recent advances in our understanding of the mechanisms of lung alveolarization and bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2019; 317:L832-L887. [PMID: 31596603 DOI: 10.1152/ajplung.00369.2019] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Bronchopulmonary dysplasia (BPD) is the most common cause of morbidity and mortality in preterm infants. A key histopathological feature of BPD is stunted late lung development, where the process of alveolarization-the generation of alveolar gas exchange units-is impeded, through mechanisms that remain largely unclear. As such, there is interest in the clarification both of the pathomechanisms at play in affected lungs, and the mechanisms of de novo alveoli generation in healthy, developing lungs. A better understanding of normal and pathological alveolarization might reveal opportunities for improved medical management of affected infants. Furthermore, disturbances to the alveolar architecture are a key histopathological feature of several adult chronic lung diseases, including emphysema and fibrosis, and it is envisaged that knowledge about the mechanisms of alveologenesis might facilitate regeneration of healthy lung parenchyma in affected patients. To this end, recent efforts have interrogated clinical data, developed new-and refined existing-in vivo and in vitro models of BPD, have applied new microscopic and radiographic approaches, and have developed advanced cell-culture approaches, including organoid generation. Advances have also been made in the development of other methodologies, including single-cell analysis, metabolomics, lipidomics, and proteomics, as well as the generation and use of complex mouse genetics tools. The objective of this review is to present advances made in our understanding of the mechanisms of lung alveolarization and BPD over the period 1 January 2017-30 June 2019, a period that spans the 50th anniversary of the original clinical description of BPD in preterm infants.
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Affiliation(s)
- Ettore Lignelli
- Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.,Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Giessen, Germany
| | - Francesco Palumbo
- Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.,Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Giessen, Germany
| | - Despoina Myti
- Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.,Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Giessen, Germany
| | - Rory E Morty
- Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.,Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Giessen, Germany
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45
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Kwon JH, Kim M, Bae YK, Kim GH, Choi SJ, Oh W, Um S, Jin HJ. Decorin Secreted by Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Induces Macrophage Polarization via CD44 to Repair Hyperoxic Lung Injury. Int J Mol Sci 2019; 20:ijms20194815. [PMID: 31569732 PMCID: PMC6801980 DOI: 10.3390/ijms20194815] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 09/24/2019] [Accepted: 09/26/2019] [Indexed: 12/18/2022] Open
Abstract
Bronchopulmonary dysplasia (BPD), caused by hyperoxia in newborns and infants, results in lung damage and abnormal pulmonary function. However, the current treatments for BPD are steroidal and pharmacological therapies, which cause neurodevelopmental impairment. Treatment with umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) is an efficient alternative approach. To prevent pulmonary inflammation in BPD, this study investigated the hypothesis that a key regulator was secreted by MSCs to polarize inflammatory macrophages into anti-inflammatory macrophages at inflammation sites. Lipopolysaccharide-induced macrophages co-cultured with MSCs secreted low levels of the inflammatory cytokines, IL-8 and IL-6, but high levels of the anti-inflammatory cytokine, IL-10. Silencing decorin in MSCs suppressed the expression of CD44, which mediates anti-inflammatory activity in macrophages. The effects of MSCs were examined in a rat model of hyperoxic lung damage. Macrophage polarization differed depending on the levels of decorin secreted by MSCs. Moreover, intratracheal injection of decorin-silenced MSCs or MSCs secreting low levels of decorin confirmed impaired alveolarization of damaged lung tissues by down-regulation of decorin. In tissues, a decrease in the anti-inflammatory macrophage marker, CD163, was observed via CD44. Thus, we identified decorin as a key paracrine factor, inducing macrophage polarization via CD44, a master immunoregulator in mesenchymal stem cells.
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Affiliation(s)
- Ji Hye Kwon
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea.
| | - Miyeon Kim
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea.
| | - Yun Kyung Bae
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea.
| | - Gee-Hye Kim
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea.
| | - Soo Jin Choi
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea.
| | - Wonil Oh
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea.
| | - Soyoun Um
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea.
| | - Hye Jin Jin
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, Korea.
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