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Gallipoli A, Unger S, El Shahed A, Fan CPS, Signorile M, Wilson D, Hoban R. Outcomes after intranasal human milk therapy in preterm infants with intraventricular hemorrhage. J Perinatol 2025; 45:202-207. [PMID: 39384614 DOI: 10.1038/s41372-024-02147-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 09/27/2024] [Accepted: 10/01/2024] [Indexed: 10/11/2024]
Abstract
OBJECTIVE Intraventricular hemorrhage (IVH) is a common cause of brain injury in preterm infants. Fresh human milk (HM) contains stem cells (SCs) that could potentially be delivered via intranasal HM (IHM). In this IHM pilot study, we describe outcomes. STUDY DESIGN Infants <33 weeks gestation with IVH were given IHM until maximum 28 days of age. Short-term neurologic outcomes and follow-up testing were compared to historic HM-fed infants. Longitudinal outcomes were plotted using linear mixed models. Weighted G-computation quantified treatment effects. Propensity score models calculated inverse probability weights for IVH grade, gestational age, and sex. RESULT 37 infants (35.1% grade 3-4 IVH) were compared to 191 historic controls (17.8% grade 3-4 IVH). Post-hemorrhagic ventricular dilatation was common (25.7% IHM patients). Most weighted outcomes, although not significant, favored IHM at 4-12 and 18 months corrected age. CONCLUSION This phase 1 study suggests powered trials of IHM for brain injury are needed. CLINICAL TRIAL REGISTRY NAME: clinicaltrials.gov identifier NCT04225286.
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Affiliation(s)
- Alessia Gallipoli
- Division of Neonatology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Sharon Unger
- Department of Paediatrics, Izaak Walton Killam Hospital, Halifax, NS, Canada
| | - Amr El Shahed
- Division of Neonatology, The Hospital for Sick Children, Toronto, ON, Canada
- University of Toronto, Toronto, ON, Canada
| | - Chun-Po Steve Fan
- Ted Rogers Computational Program, Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada
| | - Marisa Signorile
- Ted Rogers Computational Program, Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada
| | - Diane Wilson
- Division of Neonatology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Rebecca Hoban
- Division of Neonatology, The Hospital for Sick Children, Toronto, ON, Canada.
- Division of Neonatology, Seattle Children's Hospital, Seattle, WA, USA.
- University of Washington, Seattle, WA, USA.
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Hoban R, Gallipoli A, Signorile M, Mander P, Gauthier-Fisher A, Librach C, Wilson D, Unger S. Feasibility of intranasal human milk as stem cell therapy in preterm infants with intraventricular hemorrhage. J Perinatol 2024; 44:1652-1657. [PMID: 38688998 DOI: 10.1038/s41372-024-01982-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 04/15/2024] [Accepted: 04/17/2024] [Indexed: 05/02/2024]
Abstract
OBJECTIVE Intraventricular hemorrhage (IVH) is a common cause of preterm brain injury. Fresh parent's own milk (POM) contains pluripotent stem cells (SCs) that produce neuronal cells in-vitro. The permeable neonatal blood brain barrier potentially allows SC delivery. We performed the first prospective trial (clinicaltrials.gov NCT04225286) of feasibility of intranasal POM (IPOM) in preterm infants with IVH and described SC content of POM samples. STUDY DESIGN 37 Infants (mean gestation 27.7 ± 2.6 weeks, birthweight 1030 ± 320 g) with IVH (35.1% grade IV) were recruited from two tertiary Toronto NICUs. IPOM was given ideally twice daily until 28 days of age. Tolerance and adverse reactions were collected and 162 administering providers surveyed. RESULTS There were no major adverse reactions. Provider surveys suggested acceptability, although potential provider and subject stress requires further study. Milk cell analysis suggests wide variability between parents. CONCLUSIONS This phase 1 study demonstrated IPOM was tolerated and feasible in preterm infants.
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Affiliation(s)
- Rebecca Hoban
- Division of Neonatology, The Hospital for Sick Children/University of Toronto, Toronto, ON, Canada.
- Division of Neonatology, University of Washington, Seattle, WA, USA.
| | - Alessia Gallipoli
- Division of Neonatology, The Hospital for Sick Children/University of Toronto, Toronto, ON, Canada
| | - Marisa Signorile
- Ted Rogers Computational Program, Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada
| | | | | | - Clifford Librach
- CReATe Fertility Centre, Toronto, ON, Canada
- Department of Obstetrics and Gynecology, IMS and Physiology, University of Toronto, Toronto, ON, Canada
- Sunnybrook Research Institute, Toronto, ON, Canada
| | - Diane Wilson
- Division of Neonatology, The Hospital for Sick Children/University of Toronto, Toronto, ON, Canada
| | - Sharon Unger
- Department of Paediatrics, Izaak Walton Killam Hospital, Halifax, NS, Canada
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Buitrago JC, Morris SL, Backhaus A, Kaltenecker G, Kaipa JM, Girard C, Schneider S, Gruber J. Unveiling the Immunomodulatory and regenerative potential of iPSC-derived mesenchymal stromal cells and their extracellular vesicles. Sci Rep 2024; 14:24098. [PMID: 39407038 PMCID: PMC11480492 DOI: 10.1038/s41598-024-75956-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 10/09/2024] [Indexed: 10/19/2024] Open
Abstract
Induced pluripotent stem cell (iPSC)-derived mesenchymal stromal cells (iMSCs) offer a promising alternative to primary mesenchymal stromal cells (MSCs) and their derivatives, particularly extracellular vesicles (EVs), for use in advanced therapy medicinal products. In this study we evaluated the immunomodulatory and regenerative potential of iMSCs as well as iMSC-EVs, alongside primary human umbilical cord-derived mesenchymal stromal cells (hUCMSCs). Our findings demonstrate that iMSCs exhibit comparable abilities to hUCMSCs in regulating lymphocyte proliferation and inducing an anti-inflammatory phenotype in monocytes. We also observed decreased TNFα levels and increased IL-10 induction, indicating a potential mechanism for their immunomodulatory effects. Furthermore, iMSC-EVs also showed effective immunomodulation by inhibiting T cell proliferation and inducing macrophage polarization similar to their parental cells. Additionally, iMSC-EVs exhibited pro-regenerative potential akin to hUCMSC-EVs in in vitro scratch assays. Notably, priming iMSCs with pro-inflammatory cytokines significantly enhanced the immunomodulatory potential of iMSC-EVs. These results underscore the considerable promise of iMSCs and iMSCs-EVs as an alternate source for MSC-derived therapeutics, given their potent immunomodulatory and regenerative properties.
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Affiliation(s)
- July Constanza Buitrago
- Curexsys GmbH, Göttingen, Germany.
- PhD Biomedical and Biological Sciences Program, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia.
- Life Science Factory, Curexsys GmbH, Annastraβe 27, Göttingen, Germany, D-37075.
| | | | | | | | | | | | | | - Jens Gruber
- Curexsys GmbH, Göttingen, Germany.
- Life Science Factory, Curexsys GmbH, Annastraβe 27, Göttingen, Germany, D-37075.
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León-Moreno LC, Reza-Zaldívar EE, Hernández-Sapiéns MA, Villafaña-Estarrón E, García-Martin M, Ojeda-Hernández DD, Matias-Guiu JA, Gomez-Pinedo U, Matias-Guiu J, Canales-Aguirre AA. Mesenchymal Stem Cell-Based Therapies in the Post-Acute Neurological COVID Syndrome: Current Landscape and Opportunities. Biomolecules 2023; 14:8. [PMID: 38275749 PMCID: PMC10813738 DOI: 10.3390/biom14010008] [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: 11/15/2023] [Revised: 12/15/2023] [Accepted: 12/19/2023] [Indexed: 01/27/2024] Open
Abstract
One of the main concerns related to SARS-CoV-2 infection is the symptoms that could be developed by survivors, known as long COVID, a syndrome characterized by persistent symptoms beyond the acute phase of the infection. This syndrome has emerged as a complex and debilitating condition with a diverse range of manifestations affecting multiple organ systems. It is increasingly recognized for affecting the Central Nervous System, in which one of the most prevalent manifestations is cognitive impairment. The search for effective therapeutic interventions has led to growing interest in Mesenchymal Stem Cell (MSC)-based therapies due to their immunomodulatory, anti-inflammatory, and tissue regenerative properties. This review provides a comprehensive analysis of the current understanding and potential applications of MSC-based interventions in the context of post-acute neurological COVID-19 syndrome, exploring the underlying mechanisms by which MSCs exert their effects on neuroinflammation, neuroprotection, and neural tissue repair. Moreover, we discuss the challenges and considerations specific to employing MSC-based therapies, including optimal delivery methods, and functional treatment enhancements.
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Affiliation(s)
- Lilia Carolina León-Moreno
- Unidad de Evaluación Preclínica, Biotecnología Médica Farmacéutica, CONACYT Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara 44270, Mexico; (L.C.L.-M.); (M.A.H.-S.); (E.V.-E.)
| | | | - Mercedes Azucena Hernández-Sapiéns
- Unidad de Evaluación Preclínica, Biotecnología Médica Farmacéutica, CONACYT Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara 44270, Mexico; (L.C.L.-M.); (M.A.H.-S.); (E.V.-E.)
| | - Erika Villafaña-Estarrón
- Unidad de Evaluación Preclínica, Biotecnología Médica Farmacéutica, CONACYT Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara 44270, Mexico; (L.C.L.-M.); (M.A.H.-S.); (E.V.-E.)
| | - Marina García-Martin
- Laboratorio de Neurobiología, Instituto de Investigación Sanitaria, Hospital Clínico San Carlos, IdISSC, Universidad Complutense de Madrid, 28040 Madrid, Spain; (M.G.-M.); (D.D.O.-H.); (J.A.M.-G.); (U.G.-P.)
| | - Doddy Denise Ojeda-Hernández
- Laboratorio de Neurobiología, Instituto de Investigación Sanitaria, Hospital Clínico San Carlos, IdISSC, Universidad Complutense de Madrid, 28040 Madrid, Spain; (M.G.-M.); (D.D.O.-H.); (J.A.M.-G.); (U.G.-P.)
| | - Jordi A. Matias-Guiu
- Laboratorio de Neurobiología, Instituto de Investigación Sanitaria, Hospital Clínico San Carlos, IdISSC, Universidad Complutense de Madrid, 28040 Madrid, Spain; (M.G.-M.); (D.D.O.-H.); (J.A.M.-G.); (U.G.-P.)
| | - Ulises Gomez-Pinedo
- Laboratorio de Neurobiología, Instituto de Investigación Sanitaria, Hospital Clínico San Carlos, IdISSC, Universidad Complutense de Madrid, 28040 Madrid, Spain; (M.G.-M.); (D.D.O.-H.); (J.A.M.-G.); (U.G.-P.)
| | - Jorge Matias-Guiu
- Departamento de Neurología, Instituto de Investigación Sanitaria, Hospital Clínico San Carlos, IdISSC, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Alejandro Arturo Canales-Aguirre
- Unidad de Evaluación Preclínica, Biotecnología Médica Farmacéutica, CONACYT Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara 44270, Mexico; (L.C.L.-M.); (M.A.H.-S.); (E.V.-E.)
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Bruschettini M, Badura A, Romantsik O. Stem cell-based interventions for the treatment of stroke in newborn infants. Cochrane Database Syst Rev 2023; 11:CD015582. [PMID: 37994736 PMCID: PMC10666199 DOI: 10.1002/14651858.cd015582.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2023]
Abstract
BACKGROUND Perinatal stroke refers to a diverse but specific group of cerebrovascular diseases that occur between 20 weeks of fetal life and 28 days of postnatal life. Acute treatment options for perinatal stroke are limited supportive care, such as controlling hypoglycemia and seizures. Stem cell-based therapies offer a potential therapeutic approach to repair, restore, or regenerate injured brain tissue. Preclinical findings have culminated in ongoing human neonatal studies. OBJECTIVES To evaluate the benefits and harms of stem cell-based interventions for the treatment of stroke in newborn infants compared to control (placebo or no treatment) or stem-cell based interventions of a different type or source. SEARCH METHODS We searched CENTRAL, PubMed, Embase, and three trials registries in February 2023. We planned to search the reference lists of included studies and relevant systematic reviews for studies not identified by the database searches. SELECTION CRITERIA We attempted to include randomized controlled trials, quasi-randomized controlled trials, and cluster trials that evaluated any of the following comparisons. • Stem cell-based interventions (any type) versus control (placebo or no treatment) • Mesenchymal stem/stromal cells (MSCs) of a specifictype (e.g. number of doses or passages) or source (e.g. autologous/allogeneic or bone marrow/cord) versus MSCs of another type or source • Stem cell-based interventions (other than MSCs) of a specific type (e.g. mononuclear cells, oligodendrocyte progenitor cells, neural stem cells, hematopoietic stem cells, or induced pluripotent stem cell-derived cells) or source (e.g. autologous/allogeneic or bone marrow/cord) versus stem cell-based interventions (other than MSCs) of another type or source • MSCs versus stem cell-based interventions other than MSCs We planned to include all types of transplantation regardless of cell source (bone marrow, cord blood, Wharton's jelly, placenta, adipose tissue, peripheral blood), type of graft (autologous or allogeneic), and dose. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. Our primary outcomes were all-cause neonatal mortality, major neurodevelopmental disability, and immune rejection or any serious adverse event. Our secondary outcomes included all-cause mortality prior to first hospital discharge, seizures, adverse effects, and death or major neurodevelopmental disability at 18 to 24 months of age. We planned to use GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS We identified no completed or ongoing randomized trials that met our inclusion criteria. We excluded three studies: two were phase 1 trials, and one included newborn infants with conditions other than stroke (i.e. cerebral ischemia and anemia). Among the three excluded studies, we identified the first phase 1 trial on the use of stem cells for neonatal stroke. It reported that a single intranasal application of bone marrow-derived MSCs in term neonates with a diagnosis of perinatal arterial ischemic stroke (PAIS) was feasible and apparently not associated with severe adverse events. However, the trial included only 10 infants, and follow-up was limited to three months. AUTHORS' CONCLUSIONS No evidence is currently available to evaluate the benefits and harms of stem cell-based interventions for treatment of stroke in newborn infants. We identified no ongoing studies. Future clinical trials should focus on standardizing the timing and method of cell delivery and cell processing to optimize the therapeutic potential of stem cell-based interventions and safety profiles. Phase 1 and large animal studies might provide the groundwork for future randomized trials. Outcome measures should include all-cause mortality, major neurodevelopmental disability and immune rejection, and any other serious adverse events.
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Affiliation(s)
- Matteo Bruschettini
- Paediatrics, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden
- Cochrane Sweden, Department of Research and Education, Lund University, Skåne University Hospital, Lund, Sweden
| | - Anna Badura
- Department of Neonatology, University Children's Hospital Regensburg, Hospital St Hedwig of the Order of St John, University of Regensburg, Regensburg, Germany
| | - Olga Romantsik
- Paediatrics, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden
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Peng W, Yang Y, Chen J, Xu Z, Lou Y, Li Q, Zhao N, Qian K, Liu F. Small Extracellular Vesicles Secreted by iPSC-Derived MSCs Ameliorate Pulmonary Inflammation and Lung Injury Induced by Sepsis through Delivery of miR-125b-5p. J Immunol Res 2023; 2023:8987049. [PMID: 37425491 PMCID: PMC10329558 DOI: 10.1155/2023/8987049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 12/07/2022] [Accepted: 05/18/2023] [Indexed: 07/11/2023] Open
Abstract
Background Sepsis-induced acute lung injury is a common critical illness in intensive care units with no effective treatment is currently available. Small extracellular vesicles, secreted by mesenchymal stem cells (MSCs), derived from human-induced pluripotent stem cells (iMSC-sEV), possess striking advantages when incorporated MSCs and iPSCs, which are considered extremely promising cell-free therapeutic agents. However, no studies have yet been conducted to systemically examine the effects and underlying mechanisms of iMSC-sEV application on attenuated lung injury under sepsis conditions. Method iMSC-sEV were intraperitoneally administered in a rat septic lung injury model induced by cecal ligation and puncture (CLP). The efficacy of iMSC-sEV was assessed by histology, immunohistochemistry, and pro-inflammatory cytokines of bronchoalveolar lavage fluid. We also evaluated the in vitro effects of iMSC-sEV on the activation of the inflammatory response in alveolar macrophages (AMs). Small RNA sequencing was utilized to detect changes in the miRNA expression profile in lipopolysaccharide (LPS)-treated AMs after iMSC-sEV administration. The effects of miR-125b-5p on the function of AMs were studied. Results iMSC-sEV were able to attenuate pulmonary inflammation and lung injury following CLP-induced lung injury. iMSC-sEV were internalized by AMs and alleviated the release of inflammatory factors by inactivating the NF-κB signaling pathway. Moreover, miR-125b-5p showed a fold-change in LPS-treated AMs after iMSC-sEV administration and was enriched in iMSC-sEV. Mechanistically, iMSC-sEV transmitted miR-125b-5p into LPS-treated AMs to target TRAF6. Conclusion Our findings demonstrated that iMSC-sEV treatment protects against septic lung injury and exerts anti-inflammatory effects on AMs at least partially through miR-125b-5p, suggesting that iMSC-sEV may provide a novel cell-free strategy for the treatment of septic lung injury.
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Affiliation(s)
- Wei Peng
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yun Yang
- Department of Critical Care Medicine, The People's Hospital of Fengcheng City, Yichun, Jiangxi, China
| | - Jiaquan Chen
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zeyao Xu
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yuanlei Lou
- Institute of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Qi Li
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Ning Zhao
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Kejian Qian
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Fen Liu
- Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Medical Innovation Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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Valsecchi C, Croce S, Lenta E, Acquafredda G, Comoli P, Avanzini MA. TITLE: New therapeutic approaches in pediatric diseases: Mesenchymal stromal cell and mesenchymal stromal cell-derived extracellular vesicles as new drugs. Pharmacol Res 2023; 192:106796. [PMID: 37207738 DOI: 10.1016/j.phrs.2023.106796] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 05/12/2023] [Accepted: 05/16/2023] [Indexed: 05/21/2023]
Abstract
Mesenchymal Stromal Cell (MSC) clinical applications have been widely reported and their therapeutic potential has been documented in several diseases. MSCs can be isolated from several human tissues and easily expanded in vitro, they are able to differentiate in a variety of cell lineages, and they are known to interact with most immunological cells, showing immunosuppressive and tissue repair properties. Their therapeutic efficacy is closely associated with the release of bioactive molecules, namely Extracellular Vesicles (EVs), effective as their parental cells. EVs isolated from MSCs act by fusing with target cell membrane and releasing their content, showing a great potential for the treatment of injured tissues and organs, and for the modulation of the host immune system. EV-based therapies provide, as major advantages, the possibility to cross the epithelium and blood barrier and their activity is not influenced by the surrounding environment. In the present review, we deal with pre-clinical reports and clinical trials to provide data in support of MSC and EV clinical efficacy with particular focus on neonatal and pediatric diseases. Considering pre-clinical and clinical data so far available, it is likely that cell-based and cell-free therapies could become an important therapeutic approach for the treatment of several pediatric diseases.
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Affiliation(s)
- Chiara Valsecchi
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Stefania Croce
- Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Elisa Lenta
- Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Gloria Acquafredda
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Patrizia Comoli
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Maria Antonietta Avanzini
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
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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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9
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Ahn SY, Chang YS, Park WS. Stem cells for neonatal brain injury - Lessons from the bench. Semin Perinatol 2023; 47:151726. [PMID: 37003920 DOI: 10.1016/j.semperi.2023.151726] [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: 04/03/2023]
Abstract
Neonatal brain injury resulting from various intractable disorders including intraventricular hemorrhage and hypoxic ischemic encephalopathy still remains a major cause of mortality and morbidities with few effective treatments. Recent preclinical research results showing the pleiotropic neuroprotective effects of stem cell therapy, specifically mesenchymal stem cells (MSCs), suggest that MSCs transplantation might be a promising new therapeutic modality for neuroprotection against the currently intractable and devastating neonatal brain injury with complex multifactorial etiology. This review summarizes recent advances in preclinical stem cell research for treating neonatal brain injury with a focus on the important issues including the mechanism of neuroprotection, and determining the ideal cell source, route, timing and dose of MSCs transplantation.
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Affiliation(s)
- So Yoon Ahn
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea; Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, South Korea
| | - Yun Sil Chang
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea; Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, South Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAHIST), Samsung Medical Center, Seoul 06351, South Korea
| | - Won Soon Park
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea; Cell and Gene Therapy Institute, Samsung Medical Center, Seoul 06351, South Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAHIST), Samsung Medical Center, Seoul 06351, South Korea.
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10
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Cochrane Neonatal Group, Bruschettini M, Badura A, Romantsik O. Stem cell‐based interventions for the treatment of stroke in newborn infants. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2023; 2023:CD015582. [PMCID: PMC9933426 DOI: 10.1002/14651858.cd015582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the benefits and harms of stem cell‐based interventions for the treatment of stroke in newborn infants compared to control (placebo or no treatment) or stem‐cell based interventions of a different type or source.
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Affiliation(s)
| | - Matteo Bruschettini
- Department of Clinical Sciences Lund, PaediatricsLund University, Skåne University HospitalLundSweden,Cochrane SwedenLund University, Skåne University HospitalLundSweden
| | | | - Olga Romantsik
- Department of Clinical Sciences Lund, PaediatricsLund University, Skåne University HospitalLundSweden
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Romantsik O, Moreira A, Thébaud B, Ådén U, Ley D, Bruschettini M. Stem cell-based interventions for the prevention and treatment of intraventricular haemorrhage and encephalopathy of prematurity in preterm infants. Cochrane Database Syst Rev 2023; 2:CD013201. [PMID: 36790019 PMCID: PMC9932000 DOI: 10.1002/14651858.cd013201.pub3] [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] [Indexed: 02/16/2023]
Abstract
BACKGROUND Germinal matrix-intraventricular haemorrhage (GMH-IVH) and encephalopathy of prematurity (EoP) remain substantial issues in neonatal intensive care units worldwide. Current therapies to prevent or treat these conditions are limited. Stem cell-based therapies offer a potential therapeutic approach to repair, restore, or regenerate injured brain tissue. These preclinical findings have now culminated in ongoing human neonatal studies. This is an update of the 2019 review, which did not include EoP. OBJECTIVES To evaluate the benefits and harms of stem cell-based interventions for prevention or treatment of GM-IVH and EoP in preterm infants. SEARCH METHODS We used standard, extensive Cochrane search methods. The latest search was April 2022. SELECTION CRITERIA We attempted to include randomised controlled trials, quasi-randomised controlled trials, and cluster trials comparing 1. stem cell-based interventions versus control; 2. mesenchymal stromal cells (MSCs) of type or source versus MSCs of other type or source; 3. stem cell-based interventions other than MSCs of type or source versus stem cell-based interventions other than MSCs of other type or source; or 4. MSCs versus stem cell-based interventions other than MSCs. For prevention studies, we included extremely preterm infants (less than 28 weeks' gestation), 24 hours of age or less, without ultrasound diagnosis of GM-IVH or EoP; for treatment studies, we included preterm infants (less than 37 weeks' gestation), of any postnatal age, with ultrasound diagnosis of GM-IVH or with EoP. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. Our primary outcomes were 1. all-cause neonatal mortality, 2. major neurodevelopmental disability, 3. GM-IVH, 4. EoP, and 5. extension of pre-existing non-severe GM-IVH or EoP. We planned to use GRADE to assess certainty of evidence for each outcome. MAIN RESULTS We identified no studies that met our inclusion criteria. Three studies are currently registered and ongoing. Phase 1 trials are described in the 'Excluded studies' section. AUTHORS' CONCLUSIONS No evidence is currently available to evaluate the benefits and harms of stem cell-based interventions for treatment or prevention of GM-IVH or EoP in preterm infants. We identified three ongoing studies, with a sample size range from 20 to 200. In two studies, autologous cord blood mononuclear cells will be administered to extremely preterm infants via the intravenous route; in one, intracerebroventricular injection of MSCs will be administered to preterm infants up to 34 weeks' gestational age.
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Affiliation(s)
- Olga Romantsik
- Department of Clinical Sciences Lund, Paediatrics, Lund University, Skåne University Hospital, Lund, Sweden
| | - Alvaro Moreira
- Pediatrics, Division of Neonatology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Bernard Thébaud
- Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Canada
- Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research, Ottawa, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada
| | - Ulrika Ådén
- Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - David Ley
- Department of Clinical Sciences Lund, Paediatrics, Lund University, Skåne University Hospital, Lund, Sweden
| | - Matteo Bruschettini
- Department of Clinical Sciences Lund, Paediatrics, Lund University, Skåne University Hospital, Lund, Sweden
- Cochrane Sweden, Lund University, Skåne University Hospital, Lund, Sweden
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12
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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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13
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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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14
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Abas BI, Demirbolat GM, Cevik O. Wharton jelly-derived mesenchymal stem cell exosomes induce apoptosis and suppress EMT signaling in cervical cancer cells as an effective drug carrier system of paclitaxel. PLoS One 2022; 17:e0274607. [PMID: 36108271 PMCID: PMC9477505 DOI: 10.1371/journal.pone.0274607] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/30/2022] [Indexed: 11/25/2022] Open
Abstract
Mesenchymal stem cells can be obtained and multiplied from various sources and have a very high capacity to release exosomes. Exosomes are nano-sized extracellular vesicles containing biological signaling molecules. This study aimed to determine the effect of MSC-derived exosomes as a drug delivery system for paclitaxel in cervical cancer cells. In this study, human MSC were isolated from wharton jelly of umbilical cord tissue (WJ-MSC), and cells were characterized by CD44, CD90, CD105, and CD34 staining. Exosomes were released in WJ-MSC cells with serum-starved conditions for 48 hours, and particle sizes and structures were examined with zeta-sizer and TEM. In addition, exosomes CD9, CD63, and CD81 markers were checked by western blot. Paclitaxel was loaded into exosomes (Exo-PAC) by electroporation and then incubated with Hela cervical cancer cells for 24 hours. TGF-β, SMAD, Snail, Slug, β-catenin, Notch, Caspase-3, Caspase-9, Bax, Bcl-2 protein and gene expression levels were analyzed in Hela cells. As a result, low concentration Exo-PAC induced apoptosis, and suppressed epithelial-mesenchymal transition proteins in Hela cells. In this study, it has been demonstrated that WJ-MSCs can be used as drug delivery systems for cervical cancer if exosomes are produced scalably in the future.
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Affiliation(s)
- Burcin Irem Abas
- Department of Medicinal Biochemistry, School of Medicine, Aydin Adnan Menderes University, Aydin, Turkey
| | - Gulen Melike Demirbolat
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Acibadem University, Istanbul, Turkey
| | - Ozge Cevik
- Department of Medicinal Biochemistry, School of Medicine, Aydin Adnan Menderes University, Aydin, Turkey
- * E-mail:
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15
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Ojeda-Hernández DD, Hernández-Sapiéns MA, Reza-Zaldívar EE, Canales-Aguirre A, Matías-Guiu JA, Matías-Guiu J, Mateos-Díaz JC, Gómez-Pinedo U, Sancho-Bielsa F. Exosomes and Biomaterials: In Search of a New Therapeutic Strategy for Multiple Sclerosis. Life (Basel) 2022; 12:1417. [PMID: 36143453 PMCID: PMC9504193 DOI: 10.3390/life12091417] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/06/2022] [Accepted: 09/08/2022] [Indexed: 02/07/2023] Open
Abstract
Current efforts to find novel treatments that counteract multiple sclerosis (MS) have pointed toward immunomodulation and remyelination. Currently, cell therapy has shown promising potential to achieve this purpose. However, disadvantages such as poor survival, differentiation, and integration into the target tissue have limited its application. A series of recent studies have focused on the cell secretome, showing it to provide the most benefits of cell therapy. Exosomes are a key component of the cell secretome, participating in the transfer of bioactive molecules. These nano-sized vesicles offer many therapeutical advantages, such as the capacity to cross the blood-brain barrier, an enrichable cargo, and a customizable membrane. Moreover, integrating of biomaterials into exosome therapy could lead to new tissue-specific therapeutic strategies. In this work, the use of exosomes and their integration with biomaterials is presented as a novel strategy in the treatment of MS.
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Affiliation(s)
- Doddy Denise Ojeda-Hernández
- Laboratory of Neurobiology, Institute of Neurosciences, IdISSC and Hospital Clínico San Carlos, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Mercedes A. Hernández-Sapiéns
- Preclinical Evaluation Unit, Medical and Pharmaceutical Biotechnology Unit, CIATEJ-CONACyT, Guadalajara 44270, Mexico
| | - Edwin E. Reza-Zaldívar
- Tecnologico de Monterrey, The Institute for Obesity Research, Ave. General Ramón Corona 2514, Zapopan 45201, Mexico
| | - Alejandro Canales-Aguirre
- Preclinical Evaluation Unit, Medical and Pharmaceutical Biotechnology Unit, CIATEJ-CONACyT, Guadalajara 44270, Mexico
| | - Jordi A. Matías-Guiu
- Department of Neurology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Jorge Matías-Guiu
- Laboratory of Neurobiology, Institute of Neurosciences, IdISSC and Hospital Clínico San Carlos, Universidad Complutense de Madrid, 28040 Madrid, Spain
- Department of Neurology, Institute of Neurosciences, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | | | - Ulises Gómez-Pinedo
- Laboratory of Neurobiology, Institute of Neurosciences, IdISSC and Hospital Clínico San Carlos, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Francisco Sancho-Bielsa
- Área de Fisiología, Departamento de Ciencias Médicas, Facultad de Medicina de Ciudad Real, UCLM, 13071 Ciudad Real, Spain
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16
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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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17
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Kim CK, Sachdev PS, Braidy N. Recent Neurotherapeutic Strategies to Promote Healthy Brain Aging: Are we there yet? Aging Dis 2022; 13:175-214. [PMID: 35111369 PMCID: PMC8782556 DOI: 10.14336/ad.2021.0705] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 07/05/2021] [Indexed: 12/21/2022] Open
Abstract
Owing to the global exponential increase in population ageing, there is an urgent unmet need to develop reliable strategies to slow down and delay the ageing process. Age-related neurodegenerative diseases are among the main causes of morbidity and mortality in our contemporary society and represent a major socio-economic burden. There are several controversial factors that are thought to play a causal role in brain ageing which are continuously being examined in experimental models. Among them are oxidative stress and brain inflammation which are empirical to brain ageing. Although some candidate drugs have been developed which reduce the ageing phenotype, their clinical translation is limited. There are several strategies currently in development to improve brain ageing. These include strategies such as caloric restriction, ketogenic diet, promotion of cellular nicotinamide adenine dinucleotide (NAD+) levels, removal of senescent cells, 'young blood' transfusions, enhancement of adult neurogenesis, stem cell therapy, vascular risk reduction, and non-pharmacological lifestyle strategies. Several studies have shown that these strategies can not only improve brain ageing by attenuating age-related neurodegenerative disease mechanisms, but also maintain cognitive function in a variety of pre-clinical experimental murine models. However, clinical evidence is limited and many of these strategies are awaiting findings from large-scale clinical trials which are nascent in the current literature. Further studies are needed to determine their long-term efficacy and lack of adverse effects in various tissues and organs to gain a greater understanding of their potential beneficial effects on brain ageing and health span in humans.
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Affiliation(s)
- Chul-Kyu Kim
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
| | - Perminder S Sachdev
- Neuropsychiatric Institute, Euroa Centre, Prince of Wales Hospital, Sydney, Australia
| | - Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
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18
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Xi Y, Ju R, Wang Y. Mesenchymal Stem Cell-Derived Extracellular Vesicles for the Treatment of Bronchopulmonary Dysplasia. Front Pediatr 2022; 10:852034. [PMID: 35444971 PMCID: PMC9013803 DOI: 10.3389/fped.2022.852034] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 02/25/2022] [Indexed: 11/13/2022] Open
Abstract
Bronchopulmonary dysplasia (BPD) is the most common chronic respiratory disease in premature infants. However, there is a lack of effective treatment. Mesenchymal stromal cells derived extracellular vesicles (MSC-EVs), as nano- and micron-sized heterogeneous vesicles secreted by MSCs, are the main medium for information exchange between MSCs and injured tissue and organ, playing an important role in repairing tissue and organ injury. EVs include exosomes, microvesicles and so on. They are rich with various proteins, nucleic acids, and lipids. Now, EVs are considered as a new way of cell-to-cell communication. EVs mainly induce regeneration and therapeutic effects in different tissues and organs through the biomolecules they carry. The surface membrane protein or loaded protein and nucleic acid molecules carried by EVs, can activate the signal transduction of target cells and regulate the biological behavior of target cells after binding and cell internalization. MSC-EVs can promote the development of pulmonary vessels and alveoli and reduce pulmonary hypertension (PH) and inflammation and play an important role in the repair of lung injury in BPD. The regeneration potential of MSC-EVs is mainly due to the regulation of cell proliferation, survival, migration, differentiation, angiogenesis, immunoregulation, anti-inflammatory, mitochondrial activity and oxidative stress. As a new type of cell-free therapy, MSC-EVs have non-immunogenic, and are small in size and go deep into most tissues. What's more, it has good biological stability and can be modified and loaded with drugs of interest. Obviously, MSC-EVs have a good application prospect in the treatment of lung injury and BPD. However, there are still many challenges to make MSC-EVs really enter clinical application.
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Affiliation(s)
- Yufeng Xi
- Department of Neonatology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Rong Ju
- Department of Neonatology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yujia Wang
- Department of Neonatology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.,Department of Dermatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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19
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Willis GR, Reis M, Gheinani AH, Fernandez-Gonzalez A, Taglauer ES, Yeung V, Liu X, Ericsson M, Haas E, Mitsialis SA, Kourembanas S. Extracellular Vesicles Protect the Neonatal Lung from Hyperoxic Injury through the Epigenetic and Transcriptomic Reprogramming of Myeloid Cells. Am J Respir Crit Care Med 2021; 204:1418-1432. [PMID: 34699335 PMCID: PMC8865710 DOI: 10.1164/rccm.202102-0329oc] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 10/18/2021] [Indexed: 11/16/2022] Open
Abstract
Rationale: Mesenchymal stem/stromal cell (MSC)-small extracellular vesicle (MEx) treatment has shown promise in experimental models of neonatal lung injury. The molecular mechanisms by which MEx afford beneficial effects remain incompletely understood. Objectives: To investigate the therapeutic mechanism of action through assessment of MEx biodistribution and impact on immune cell phenotypic heterogeneity. Methods: MEx were isolated from the conditioned medium of human umbilical cord Wharton's jelly-derived MSCs. Newborn mice were exposed to hyperoxia (HYRX, 75% O2) from birth and returned to room air at Postnatal Day 14 (PN14). Mice received either a bolus intravenous MEx dose at PN4 or bone marrow-derived myeloid cells (BMDMy) pretreated with MEx. Animals were killed at PN4, PN7, PN14, or PN28 to characterize MEx biodistribution or for assessment of pulmonary parameters. The therapeutic role of MEx-educated BMDMy was determined in vitro and in vivo. Measurements and Main Results: MEx therapy ameliorated core histological features of HYRX-induced neonatal lung injury. Biodistribution and mass cytometry studies demonstrated that MEx localize in the lung and interact with myeloid cells. MEx restored the apportion of alveolar macrophages in the HYRX-injured lung and concomitantly suppressed inflammatory cytokine production. In vitro and ex vivo studies revealed that MEx promoted an immunosuppressive BMDMy phenotype. Functional assays demonstrated that the immunosuppressive actions of BMDMy are driven by phenotypically and epigenetically reprogrammed monocytes. Adoptive transfer of MEx-educated BMDMy, but not naive BMDMy, restored alveolar architecture, blunted fibrosis and pulmonary vascular remodeling, and improved exercise capacity. Conclusions: MEx ameliorate hyperoxia-induced neonatal lung injury though epigenetic and phenotypic reprogramming of myeloid cells.
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Affiliation(s)
- Gareth R. Willis
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
| | - Monica Reis
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
| | - Ali Hashemi Gheinani
- Department of Urology, Boston Children’s Hospital, Boston, Massachusetts
- Department of Surgery, Harvard Medical School, Boston, Massachusetts
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts
| | - Angeles Fernandez-Gonzalez
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
| | - Elizabeth S. Taglauer
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
| | - Vincent Yeung
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
| | - Xianlan Liu
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts
| | - Maria Ericsson
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts; and
| | - Eric Haas
- Mass Cytometry Core, Dana Farber Cancer Institute, Boston, Massachusetts
| | - S. Alex Mitsialis
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
| | - Stella Kourembanas
- Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
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20
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Kabatas S, Civelek E, Savrunlu EC, Kaplan N, Boyalı O, Diren F, Can H, Genç A, Akkoç T, Karaöz E. Feasibility of allogeneic mesenchymal stem cells in pediatric hypoxic-ischemic encephalopathy: Phase I study. World J Stem Cells 2021; 13:470-484. [PMID: 34136076 PMCID: PMC8176840 DOI: 10.4252/wjsc.v13.i5.470] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 02/26/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of death and long-term neurological impairment in the pediatric population. Despite a limited number of treatments to cure HIE, stem cell therapies appear to be a potential treatment option for brain injury resulting from HIE.
AIM To investigate the efficacy and safety of stem cell-based therapies in pediatric patients with HIE.
METHODS The study inclusion criteria were determined as the presence of substantial deficit and disability caused by HIE. Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) were intrathecally (IT), intramuscularly (IM), and intravenously administered to participants at a dose of 1 × 106/kg for each administration route twice monthly for 2 mo. In different follow-up durations, the effect of WJ-MSCs administration on HIE, the quality of life, prognosis of patients, and side effects were investigated, and patients were evaluated for neurological, cognitive functions, and spasticity using the Wee Functional Independence Measure (Wee FIM) Scale and Modified Ashworth (MA) Scale.
RESULTS For all participants (n = 6), the mean duration of exposure to hypoxia was 39.17 + 18.82 min, the mean time interval after HIE was 21.83 ± 26.60 mo, the mean baseline Wee FIM scale score was 13.5 ± 0.55, and the mean baseline MA scale score was 35 ± 9.08. Three patients developed only early complications such as low-grade fever, mild headache associated with IT injection, and muscle pain associated with IM injection, all of which were transient and disappeared within 24 h. The treatment was evaluated to be safe and effective as demonstrated by magnetic resonance imaging examinations, electroencephalographies, laboratory tests, and neurological and functional scores of patients. Patients exhibited significant improvements in all neurological functions through a 12-mo follow-up. The mean Wee FIM scale score of participants increased from 13.5 ± 0.55 to 15.17 ± 1.6 points (mean ± SD) at 1 mo (z = - 1.826, P = 0.068) and to 23.5 ± 3.39 points at 12 mo (z = -2.207, P = 0.027) post-treatment. The percentage of patients who achieved an excellent functional improvement (Wee FIM scale total score = 126) increased from 10.71% (at baseline) to 12.03% at 1 mo and to 18.65% at 12 mo post-treatment.
CONCLUSION Both the triple-route and multiple WJ-MSC implantations were safe and effective in pediatric patients with HIE with significant neurological and functional improvements. The results of this study support conducting further randomized, placebo-controlled studies on this treatment in the pediatric population.
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Affiliation(s)
- Serdar Kabatas
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, Istanbul 34255, Turkey
- Pediatric Allergy-Immunology, Marmara University, Institute of Health Sciences, Istanbul 34854, Turkey
- Center for Stem Cell & Gene Therapy Research and Practice, University of Health Sciences, Istanbul 34255, Turkey
| | - Erdinç Civelek
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, Istanbul 34255, Turkey
- Pediatric Allergy-Immunology, Marmara University, Institute of Health Sciences, Istanbul 34854, Turkey
| | - Eyüp Can Savrunlu
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, Istanbul 34255, Turkey
| | - Necati Kaplan
- Department of Neurosurgery, Istanbul Rumeli University, Çorlu Reyap Hospital, Tekirdağ 59860, Turkey
| | - Osman Boyalı
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, Istanbul 34255, Turkey
| | - Furkan Diren
- Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, Istanbul 34255, Turkey
| | - Halil Can
- Department of Neurosurgery, Istanbul Biruni University, Faculty of Medicine, Istanbul 34010, Turkey
- Department of Neurosurgery, Istanbul Medicine Hospital, Istanbul 34203, Turkey
| | - Ali Genç
- Department of Neurosurgery, Istanbul Asya Hospital, Istanbul 34250, Turkey
| | - Tunç Akkoç
- Pediatric Allergy-Immunology, Marmara University, Istanbul 34899, Turkey
| | - Erdal Karaöz
- Center for Regenerative Medicine and Stem Cell Research & Manufacturing (LivMedCell), Liv Hospital, Istanbul 34340, Turkey
- Department of Histology and Embryology, Istinye University, Faculty of Medicine, Istanbul 34010, Turkey
- Center for Stem Cell and Tissue Engineering Research and Practice, Istinye University, Istanbul 34340, Turkey
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21
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Chia WK, Cheah FC, Abdul Aziz NH, Kampan NC, Shuib S, Khong TY, Tan GC, Wong YP. A Review of Placenta and Umbilical Cord-Derived Stem Cells and the Immunomodulatory Basis of Their Therapeutic Potential in Bronchopulmonary Dysplasia. Front Pediatr 2021; 9:615508. [PMID: 33791258 PMCID: PMC8006350 DOI: 10.3389/fped.2021.615508] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 02/17/2021] [Indexed: 12/13/2022] Open
Abstract
Bronchopulmonary dysplasia (BPD) is a devastating lung disorder of preterm infants as a result of an aberrant reparative response following exposures to various antenatal and postnatal insults. Despite sophisticated medical treatment in this modern era, the incidence of BPD remains unabated. The current strategies to prevent and treat BPD have met with limited success. The emergence of stem cell therapy may be a potential breakthrough in mitigating this complex chronic lung disorder. Over the last two decades, the human placenta and umbilical cord have gained increasing attention as a highly potential source of stem cells. Placenta-derived stem cells (PDSCs) and umbilical cord-derived stem cells (UCDSCs) display several advantages such as immune tolerance and are generally devoid of ethical constraints, in addition to their stemness qualities. They possess the characteristics of both embryonic and mesenchymal stromal/stem cells. Recently, there are many preclinical studies investigating the use of these cells as therapeutic agents in neonatal disease models for clinical applications. In this review, we describe the preclinical and clinical studies using PDSCs and UCDSCs as treatment in animal models of BPD. The source of these stem cells, routes of administration, and effects on immunomodulation, inflammation and regeneration in the injured lung are also discussed. Lastly, a brief description summarized the completed and ongoing clinical trials using PDSCs and UCDSCs as therapeutic agents in preventing or treating BPD. Due to the complexity of BPD, the development of a safe and efficient therapeutic agent remains a major challenge to both clinicians and researchers.
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Affiliation(s)
- Wai Kit Chia
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Fook Choe Cheah
- Department of Pediatrics, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nor Haslinda Abdul Aziz
- Department of Obstetrics and Gynecology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nirmala Chandralega Kampan
- Department of Obstetrics and Gynecology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Salwati Shuib
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Teck Yee Khong
- Department of Pathology, SA Pathology, Women's and Children's Hospital, Adelaide, SA, Australia
| | - Geok Chin Tan
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Yin Ping Wong
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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22
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Villatoro AJ, Martín-Astorga MDC, Alcoholado C, Becerra J. Canine colostrum exosomes: characterization and influence on the canine mesenchymal stem cell secretory profile and fibroblast anti-oxidative capacity. BMC Vet Res 2020; 16:417. [PMID: 33138803 PMCID: PMC7607682 DOI: 10.1186/s12917-020-02623-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 10/13/2020] [Indexed: 02/07/2023] Open
Abstract
Background Canine colostrum milk (CCM) is a specific secretion of the mammary gland that is fundamental for the survival of the newborn. CCM has many described components (immunoglobulins, proteins or fat), but its small vesicles, named exosomes, are largely unknown. Results A characterization of CCM exosomes was performed. Exosomes were abundant in CCM and appeared with the characteristic cup-shaped morphology and well-defined round vesicles. The size distribution of exosomes was between 37 and 140 nm, and western blot analysis showed positive expression of specific exosomal markers. Proteomic analysis revealed a total of 826 proteins in exosome cargo. We also found that exosomes modified the proliferation and secretory profiles in canine mesenchymal stem cells derived from bone marrow (cBM-MSCs) and adipose tissue (cAd-MSCs). Additionally, CCM exosomes demonstrated a potent antioxidant effect on canine fibroblasts in culture. Conclusions Our findings highlight, for the first time, the abundant presence of exosomes in CCM and their ability to interact with mesenchymal stem cells (MSCs). The addition of exosomes to two types of MSCs in culture resulted in specific secretory profiles with functions related to angiogenesis, migration and chemotaxis of immune cells. In particular, the cAd-MSCs secretory profile showed higher potential in adipose tissue development and neurogenesis, while cBM-MSC production was associated with immunity, cell mobilization and haematopoiesis. Finally, exosomes also presented antioxidant capacity on fibroblasts against reactive oxygen species activity within the cell, demonstrating their fundamental role in the development and maturation of dogs in the early stages of their life. Supplementary information Supplementary information accompanies this paper at 10.1186/s12917-020-02623-w.
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Affiliation(s)
- Antonio J Villatoro
- Laboratory of Bioengineering and Tissue Regeneration (LABRET), Department of Cell Biology, Genetics and Physiology, Faculty of Sciences, University of Málaga, IBIMA, 29071, Málaga, Spain.,Instituto de Immunología Clínica y Terapia Celular (IMMUNESTEM), Miraflores del Palo, 14, 29018, Málaga, Spain
| | - María Del Carmen Martín-Astorga
- Laboratory of Bioengineering and Tissue Regeneration (LABRET), Department of Cell Biology, Genetics and Physiology, Faculty of Sciences, University of Málaga, IBIMA, 29071, Málaga, Spain
| | - Cristina Alcoholado
- Laboratory of Bioengineering and Tissue Regeneration (LABRET), Department of Cell Biology, Genetics and Physiology, Faculty of Sciences, University of Málaga, IBIMA, 29071, Málaga, Spain.,Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029, Madrid, Spain
| | - José Becerra
- Laboratory of Bioengineering and Tissue Regeneration (LABRET), Department of Cell Biology, Genetics and Physiology, Faculty of Sciences, University of Málaga, IBIMA, 29071, Málaga, Spain. .,Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029, Madrid, Spain. .,Andalusian Centre for Nanomedicine and Biotechnology-BIONAND, Severo Ochoa 35, 29590, Málaga, Spain.
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23
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Taglauer ES, Fernandez-Gonzalez A, Willis GR, Reis M, Yeung V, Liu X, Mitsialis SA, Kourembanas S. Mesenchymal stromal cell-derived extracellular vesicle therapy prevents preeclamptic physiology through intrauterine immunomodulation†. Biol Reprod 2020; 104:457-467. [PMID: 33112369 DOI: 10.1093/biolre/ioaa198] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 09/29/2020] [Accepted: 10/23/2020] [Indexed: 12/17/2022] Open
Abstract
Human umbilical cord-derived mesenchymal stromal cells (MSCs) are a widely recognized treatment modality for a variety of preclinical disease models and have been transitioned to human clinical trials. We have previously shown in neonatal lung disease that the therapeutic capacity of MSCs is conferred by their secreted extracellular vesicles (MEx), which function primarily through immunomodulation. We hypothesize that MEx have significant therapeutic potential pertinent to immune-mediated gestational diseases. Of particular interest is early-onset preeclampsia, which can be caused by alterations of the maternal intrauterine immune environment. Using a heme-oxygenase-1 null mouse model of pregnancy loss with preeclampsia-like features, we examined the preventative effects of maternal MEx treatment early in pregnancy. Heme oxygenase-1 null females (Hmox1-/-) or wild-type control females were bred in homozygous matings followed by evaluation of maternal and fetal parameters. A single dose of MEx was administered intravenously on gestational day (GD)1 to Hmox1-/- females (Hmox1-/- MEx). Compared with untreated Hmox1-/- females, Hmox1-/- MEx-treated pregnancies showed significant improvement in fetal loss, intrauterine growth restriction, placental spiral artery modification, and maternal preeclamptic stigmata. Biodistribution studies demonstrated that MEx localize to a subset of cells in the preimplantation uterus. Further, mass cytometric (CyTOF) evaluation of utero-placental leukocytes in Hmox1-/- MEx versus untreated pregnancies showed alteration in the abundance, surface marker repertoire, and cytokine profiles of multiple immune populations. Our data demonstrate the therapeutic potential of MEx to optimize the intrauterine immune environment and prevent maternal and fetal sequelae of preeclamptic disease.
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Affiliation(s)
- Elizabeth S Taglauer
- Division of Newborn Medicine and 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 and Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.,Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Gareth R Willis
- Division of Newborn Medicine and Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.,Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Monica Reis
- Division of Newborn Medicine and Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.,Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Vincent Yeung
- Division of Newborn Medicine and Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.,Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Xianlan Liu
- Division of Newborn Medicine and 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 and 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 and Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.,Department of Pediatrics, Harvard Medical School, Boston, MA, USA
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24
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Bruschettini M, Romantsik O, Moreira A, Ley D, Thébaud B. Stem cell-based interventions for the prevention of morbidity and mortality following hypoxic-ischaemic encephalopathy in newborn infants. Cochrane Database Syst Rev 2020; 8:CD013202. [PMID: 32813884 PMCID: PMC7438027 DOI: 10.1002/14651858.cd013202.pub2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hypoxic-ischaemic encephalopathy (HIE) is a leading cause of mortality and long-term neurological sequelae, affecting thousands of children worldwide. Current therapies to treat HIE are limited to cooling. Stem cell-based therapies offer a potential therapeutic approach to repair or regenerate injured brain tissue. These preclinical findings have now culminated in ongoing human neonatal trials. OBJECTIVES To determine the efficacy and safety of stem cell-based interventions for the treatment of hypoxic-ischaemic encephalopathy (HIE) in newborn infants. SEARCH METHODS We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 5), MEDLINE via PubMed (1966 to 8 June 2020), Embase (1980 to 8 June 2020), and CINAHL (1982 to 8 June 2020). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA Randomised controlled trials, quasi-randomised controlled trials and cluster trials comparing 1) stem cell-based interventions (any type) compared to control (placebo or no treatment); 2) use of mesenchymal stem/stromal cells (MSCs) of type (e.g. number of doses or passages) or source (e.g. autologous versus allogeneic, or bone marrow versus cord) versus MSCs of other type or source; 3) use of stem cell-based interventions other than MSCs of type (e.g. mononuclear cells, oligodendrocyte progenitor cells, neural stem cells, hematopoietic stem cells, and inducible pluripotent stem cells) or source (e.g. autologous versus allogeneic, or bone marrow versus cord) versus stem cell-based interventions other than MSCs of other type or source; or 4) MSCs versus stem cell-based interventions other than MSCs. DATA COLLECTION AND ANALYSIS For each of the included trials, two authors independently planned to extract data (e.g. number of participants, birth weight, gestational age, type and source of MSCs or other stem cell-based interventions) and assess the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow-up). The primary outcomes considered in this review are all-cause neonatal mortality, major neurodevelopmental disability, death or major neurodevelopmental disability assessed at 18 to 24 months of age. We planned to use the GRADE approach to assess the quality of evidence. MAIN RESULTS Our search strategy yielded 616 references. Two review authors independently assessed all references for inclusion. We did not find any completed studies for inclusion. Fifteen RCTs are currently registered and ongoing. We describe the three studies we excluded. AUTHORS' CONCLUSIONS There is currently no evidence from randomised trials that assesses the benefit or harms of stem cell-based interventions for the prevention of morbidity and mortality following hypoxic-ischaemic encephalopathy in newborn infants.
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Affiliation(s)
- Matteo Bruschettini
- Department of Clinical Sciences Lund, Paediatrics, Lund University, Skåne University Hospital, Lund, Sweden
- Cochrane Sweden, Lund University, Skåne University Hospital, Lund, Sweden
| | - Olga Romantsik
- Department of Clinical Sciences Lund, Paediatrics, Lund University, Skåne University Hospital, Lund, Sweden
| | - Alvaro Moreira
- Pediatrics, Division of Neonatology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - David Ley
- Department of Clinical Sciences Lund, Paediatrics, Lund University, Skåne University Hospital, Lund, Sweden
| | - Bernard Thébaud
- Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Canada
- Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research, Ottawa, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada
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25
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Willis GR, Fernandez-Gonzalez A, Reis M, Yeung V, Liu X, Ericsson M, Andrews NA, Mitsialis SA, Kourembanas S. Mesenchymal stromal cell-derived small extracellular vesicles restore lung architecture and improve exercise capacity in a model of neonatal hyperoxia-induced lung injury. J Extracell Vesicles 2020; 9:1790874. [PMID: 32939235 PMCID: PMC7480622 DOI: 10.1080/20013078.2020.1790874] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Early administration of mesenchymal stromal cell (MSC)-derived small extracellular vesicles (MEx) has shown considerable promise in experimental models of bronchopulmonary dysplasia (BPD). However, the ability of MEx to reverse the long-term pulmonary complications associated with established BPD remains unknown. In this study, MEx were isolated from media conditioned by human Wharton’s Jelly-derived MSC cultures. Newborn mice (FVB strain) were exposed to hyperoxia (HYRX (75% O2)) before returning to room air at postnatal day 14 (PN14). Following prolonged HYRX-exposure, animals received a single MEx dose at PN18 or serial MEx treatments at PN18-39 (“late” intervention). This group was compared to animals that received an early single MEx dose at PN4 (“early” intervention). Animals were harvested at PN28 or 60 for assessment of pulmonary parameters. We found that early and late MEx interventions effectively ameliorated core features of HYRX-induced neonatal lung injury, improving alveolar simplification, pulmonary fibrosis, vascular remodelling and blood vessel loss. Exercise capacity testing and assessment of pulmonary hypertension (PH) showed functional improvements following both early and late MEx interventions. In conclusion, delivery of MEx following prolonged HYRX-exposure improves core features of experimental BPD, restoring lung architecture, decreasing pulmonary fibrosis and vascular muscularization, ameliorating PH and improving exercise capacity. Taken together, delivery of MEx may not only be effective in the immediate neonatal period to prevent the development of BPD but may provide beneficial effects for the management and potentially the reversal of cardiorespiratory complications in infants and children with established BPD.
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Affiliation(s)
- Gareth R Willis
- 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
| | - Monica Reis
- Division of Newborn Medicine & Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.,Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Vincent Yeung
- Division of Newborn Medicine & Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.,Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Xianlan Liu
- Division of Newborn Medicine & Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA
| | - Maria Ericsson
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Nick A Andrews
- F.M. Kirby Center for Neurobiology, Harvard Medical School, Boston Children's Hospital, 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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26
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Liau LL, Al-Masawa ME, Koh B, Looi QH, Foo JB, Lee SH, Cheah FC, Law JX. The Potential of Mesenchymal Stromal Cell as Therapy in Neonatal Diseases. Front Pediatr 2020; 8:591693. [PMID: 33251167 PMCID: PMC7672022 DOI: 10.3389/fped.2020.591693] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/05/2020] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) can be derived from various tissue sources, such as the bone marrow (BMSCs), adipose tissue (ADSCs), umbilical cord (UC-MSCs) and umbilical cord blood (UCB-MSCs). Clinical trials have been conducted to investigate the potential of MSCs in ameliorating neonatal diseases, including bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH) and necrotizing enterocolitis (NEC). In preclinical studies, MSC therapy has been tested for the treatment of various neonatal diseases affecting the heart, eye, gut, and brain as well as sepsis. Up to date, the number of clinical trials using MSCs to treat neonatal diseases is still limited. The data reported thus far positioned MSC therapy as safe with positive outcomes. However, most of these trials are still preliminary and generally smaller in scale. Larger trials with more appropriate controls and a longer follow-up period need to be conducted to prove the safety and efficacy of the therapy more conclusively. This review discusses the current application of MSCs in treating neonatal diseases, its mechanism of action and future direction of this novel therapy, including the potential of using MSC-derived extracellular vesicles instead of the cells to treat various clinical conditions in the newborn.
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Affiliation(s)
- Ling Ling Liau
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Maimonah Eissa Al-Masawa
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Benson Koh
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Qi Hao Looi
- Future Cytohealth Sdn Bhd, Bandar Seri Petaling, Kuala Lumpur, Malaysia
| | - Jhi Biau Foo
- School of Pharmacy, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
| | - Sau Har Lee
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
| | - Fook Choe Cheah
- Department of Paediatrics, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Jia Xian Law
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
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27
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Romantsik O, Bruschettini M, Moreira A, Thébaud B, Ley D, Cochrane Neonatal Group. Stem cell-based interventions for the prevention and treatment of germinal matrix-intraventricular haemorrhage in preterm infants. Cochrane Database Syst Rev 2019; 9:CD013201. [PMID: 31549743 PMCID: PMC6757514 DOI: 10.1002/14651858.cd013201.pub2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Germinal matrix-intraventricular haemorrhage (GMH-IVH) remains a substantial issue in neonatal intensive care units worldwide. Current therapies to prevent or treat GMH-IVH are limited. Stem cell-based therapies offer a potential therapeutic approach to repair, restore, and/or regenerate injured brain tissue. These preclinical findings have now culminated in ongoing human neonatal studies. OBJECTIVES To determine the benefits and harms of stem cell-based interventions for prevention or treatment of germinal matrix-intraventricular haemorrhage (GM-IVH) in preterm infants. SEARCH METHODS We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 1), in the Cochrane Library; MEDLINE via PubMed (1966 to 7 January 2019); Embase (1980 to 7 January 2019); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 7 January 2019). We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA We attempted to identify randomised controlled trials, quasi-randomised controlled trials, and cluster trials comparing (1) stem cell-based interventions versus control; (2) mesenchymal stromal cells (MSCs) of type or source versus MSCs of other type or source; (3) stem cell-based interventions other than MSCs of type or source versus stem cell-based interventions other than MSCs of other type or source; or (4) MSCs versus stem cell-based interventions other than MSCs. For prevention studies, we included extremely preterm infants (less than 28 weeks' gestation), 24 hours of age or less, without ultrasound diagnosis of GM-IVH; for treatment studies, we included preterm infants (less than 37 weeks' gestation), of any postnatal age, with ultrasound diagnosis of GM-IVH. DATA COLLECTION AND ANALYSIS For each of the included trials, two review authors independently planned to extract data (e.g. number of participants, birth weight, gestational age, type and source of MSCs, other stem cell-based interventions) and assess the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow-up). Primary outcomes considered in this review are all-cause neonatal mortality, major neurodevelopmental disability, GM-IVH, and extension of pre-existing non-severe GM-IVH. We planned to use the GRADE approach to assess the quality of evidence. MAIN RESULTS Our search strategy yielded 769 references. We did not find any completed studies for inclusion. One randomised controlled trial is currently registered and ongoing. Five phase 1 trials are described in the excluded studies. AUTHORS' CONCLUSIONS Currently no evidence is available to show the benefits or harms of stem cell-based interventions for treatment or prevention of GM-IVH in preterm infants.
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Affiliation(s)
- Olga Romantsik
- Lund University, Skåne University HospitalDepartment of Clinical Sciences Lund, PaediatricsLundSweden
| | - Matteo Bruschettini
- Lund University, Skåne University HospitalDepartment of Clinical Sciences Lund, PaediatricsLundSweden
- Skåne University HospitalCochrane SwedenWigerthuset, Remissgatan 4, first floorroom 11‐221LundSweden22185
| | - Alvaro Moreira
- University of Texas Health Science Center at San AntonioPediatrics, Division of NeonatologySan AntonioTexasUSA
| | - Bernard Thébaud
- Children's Hospital of Eastern OntarioDepartment of PediatricsOttawaONCanada
- Ottawa Hospital Research Institute, Sprott Centre for Stem Cell ResearchOttawaCanada
- University of OttawaDepartment of Cellular and Molecular MedicineOttawaCanada
| | - David Ley
- Lund University, Skane University HospitalDepartment of Clinical Sciences Lund, PaediatricsLundSweden
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28
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Bao L, Shi Y. [Mesenchymal stem cell transplantation in the treatment of bronchopulmonary dysplasia: opportunities and challenges]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2019; 21:619-623. [PMID: 31315757 PMCID: PMC7389107 DOI: 10.7499/j.issn.1008-8830.2019.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 05/06/2019] [Indexed: 06/10/2023]
Abstract
Bronchopulmonary dysplasia (BPD) is one of the most common chronic lung diseases in neonates especially in preterm infants. It is also the main reason leading to a poor prognosis. The prognosis of the neonates with BPD is unsatisfactory with current treatment strategies. Recent clinical trails have found that mesenchymal stem cell (MSC) transplantation might be effective and promising for treatment of BPD in neonates. This article outlines the characteristics of MSC and the potential mechanisms of MSC transplantation for BPD in vivo, and the safety and feasibility of MSC transplantation in BPD neonates, as well as the challenges in clinical trials on MSC transplantation for treatment of BPD.
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Affiliation(s)
- Lei Bao
- Department of Neonatology, Children's Hospital of Chongqing Medical University/Ministry of Education Key Laboratory of Child Development and Disorders/China International Science and Technology Cooperation Base of Child Development and Critical Disorders/Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing 400014, China.
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29
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Abstract
Cerebral palsy occurs more often in preterm than in term deliveries and is one of the major neurologic injuries seen in preterm infants. Magnesium sulfate has been found to reduce the risk of cerebral palsy in patients at risk of delivery before 32 weeks' gestational age. Multiple large clinical trials have shown this effect. The authors recommend magnesium sulfate bolus followed by continuous dosing of magnesium sulfate in those at risk of delivery before 32 weeks' gestation until delivery occurs or is no longer imminent. This article also discusses novel and emerging therapies for the prevention of cerebral palsy.
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Affiliation(s)
- Rebecca A Jameson
- Department of Obstetrics and Gynecology, The State University of New York Upstate Medical University, 750 East Adams Street, 2204 Weiskotten Hall, Syracuse, NY 13210, USA
| | - Helene B Bernstein
- Department of Obstetrics and Gynecology, The State University of New York Upstate Medical University, 750 East Adams Street, 2204 Weiskotten Hall, Syracuse, NY 13210, USA; Department of Microbiology and Immunology, The State University of New York Upstate Medical University, 750 East Adams Street, 2204 Weiskotten Hall, Syracuse, NY 13210, USA.
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30
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Willis GR, Fernandez-Gonzalez A, Anastas J, Vitali SH, Liu X, Ericsson M, Kwong A, Mitsialis SA, Kourembanas S. Mesenchymal Stromal Cell Exosomes Ameliorate Experimental Bronchopulmonary Dysplasia and Restore Lung Function through Macrophage Immunomodulation. Am J Respir Crit Care Med 2019; 197:104-116. [PMID: 28853608 DOI: 10.1164/rccm.201705-0925oc] [Citation(s) in RCA: 445] [Impact Index Per Article: 74.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
RATIONALE Mesenchymal stem/stromal cell (MSC) therapies have shown promise in preclinical models of pathologies relevant to newborn medicine, such as bronchopulmonary dysplasia (BPD). We have reported that the therapeutic capacity of MSCs is comprised in their secretome, and demonstrated that the therapeutic vectors are exosomes produced by MSCs (MSC-exos). OBJECTIVES To assess efficacy of MSC-exo treatment in a preclinical model of BPD and to investigate mechanisms underlying MSC-exo therapeutic action. METHODS Exosomes were isolated from media conditioned by human MSC cultures. Newborn mice were exposed to hyperoxia (HYRX; 75% O2), treated with exosomes on Postnatal Day (PN) 4 and returned to room air on PN7. Treated animals and appropriate controls were harvested on PN7, -14, or -42 for assessment of pulmonary parameters. MEASUREMENTS AND MAIN RESULTS HYRX-exposed mice presented with pronounced alveolar simplification, fibrosis, and pulmonary vascular remodeling, which was effectively ameliorated by MSC-exo treatment. Pulmonary function tests and assessment of pulmonary hypertension showed functional improvements after MSC-exo treatment. Lung mRNA sequencing demonstrated that MSC-exo treatment induced pleiotropic effects on gene expression associated with HYRX-induced inflammation and immune responses. MSC-exos modulate the macrophage phenotype fulcrum, suppressing the proinflammatory "M1" state and augmenting an antiinflammatory "M2-like" state, both in vitro and in vivo. CONCLUSIONS MSC-exo treatment blunts HYRX-associated inflammation and alters the hyperoxic lung transcriptome. This results in alleviation of HYRX-induced BPD, improvement of lung function, decrease in fibrosis and pulmonary vascular remodeling, and amelioration of pulmonary hypertension. The MSC-exo mechanism of action is associated with modulation of lung macrophage phenotype.
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Affiliation(s)
- Gareth R Willis
- 1 Division of Newborn Medicine, Department of Medicine, and.,2 Department of Pediatrics and
| | | | - Jamie Anastas
- 1 Division of Newborn Medicine, Department of Medicine, and.,3 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts
| | - Sally H Vitali
- 4 Division of Critical Care Medicine, Department of Anesthesia, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, Massachusetts; and.,2 Department of Pediatrics and
| | - Xianlan Liu
- 1 Division of Newborn Medicine, Department of Medicine, and
| | - Maria Ericsson
- 3 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts
| | - April Kwong
- 1 Division of Newborn Medicine, Department of Medicine, and
| | - S Alex Mitsialis
- 1 Division of Newborn Medicine, Department of Medicine, and.,2 Department of Pediatrics and
| | - Stella Kourembanas
- 1 Division of Newborn Medicine, Department of Medicine, and.,2 Department of Pediatrics and
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Porzionato A, Zaramella P, Dedja A, Guidolin D, Van Wemmel K, Macchi V, Jurga M, Perilongo G, De Caro R, Baraldi E, Muraca M. Intratracheal administration of clinical-grade mesenchymal stem cell-derived extracellular vesicles reduces lung injury in a rat model of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2019; 316:L6-L19. [DOI: 10.1152/ajplung.00109.2018] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) prevent the onset of bronchopulmonary dysplasia (BPD) in animal models, an effect that seems to be mediated by their secreted extracellular vesicles (EVs). The aim of this study was to compare the protective effects of intratracheally (IT) administered MSCs versus MSC-EVs in a hyperoxia-induced rat model of BPD. At birth, rats were distributed as follows: animals raised in ambient air for 2 wk ( n = 10), and animals exposed to 60% oxygen for 2 wk and treated with IT-administered physiological solution ( n = 10), MSCs ( n = 10), or MSC-EVs ( n = 10) on postnatal days 3, 7, and 10. The sham-treated hyperoxia-exposed animals showed reductions in total surface area of alveolar air spaces, and total number of alveoli ( Nalv), and an increased mean alveolar volume (Valv). EVs prompted a significant increase in Nalv ( P < 0.01) and a significant decrease in Valv ( P < 0.05) compared with sham-treated animals, whereas MSCs only significantly improved Nalv ( P < 0.05). Small pulmonary vessels of the sham-treated hyperoxia-exposed rats also showed an increase in medial thickness, which only EVs succeeded in preventing significantly ( P < 0.05). In conclusion, both EVs and MSCs reduce hyperoxia-induced damage, with EVs obtaining better results in terms of alveolarization and lung vascularization parameters. This suggests that IT-administered EVs could be an effective approach to BPD treatment.
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Affiliation(s)
- Andrea Porzionato
- Human Anatomy Section, Department of Neurosciences, University of Padova, Padua, Italy
| | - Patrizia Zaramella
- Neonatal Intensive Care Unit, Department of Women’s and Children’s Health, University of Padova, Padua, Italy
| | - Arben Dedja
- Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padua, Italy
| | - Diego Guidolin
- Human Anatomy Section, Department of Neurosciences, University of Padova, Padua, Italy
| | | | - Veronica Macchi
- Human Anatomy Section, Department of Neurosciences, University of Padova, Padua, Italy
| | - Marcin Jurga
- The Cell Factory BVBA (Esperite NV), Niel, Belgium
| | - Giorgio Perilongo
- Pediatric Clinic, Department of Women’s and Children’s Health, University of Padova, Padua, Italy
- Institute of Pediatric Research, “Città della Speranza,” Padua, Italy
| | - Raffaele De Caro
- Human Anatomy Section, Department of Neurosciences, University of Padova, Padua, Italy
| | - Eugenio Baraldi
- Neonatal Intensive Care Unit, Department of Women’s and Children’s Health, University of Padova, Padua, Italy
- Institute of Pediatric Research, “Città della Speranza,” Padua, Italy
| | - Maurizio Muraca
- Institute of Pediatric Research, “Città della Speranza,” Padua, Italy
- Stem Cell and Regenerative Medicine Laboratory, Department of Women’s and Children’s Health, University of Padova, Padua, Italy
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Burgess JK, Heijink IH. Paving the Road for Mesenchymal Stem Cell-Derived Exosome Therapy in Bronchopulmonary Dysplasia and Pulmonary Hypertension. STEM CELL-BASED THERAPY FOR LUNG DISEASE 2019. [PMCID: PMC7122497 DOI: 10.1007/978-3-030-29403-8_8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Bronchopulmonary dysplasia (BPD) is a chronic neonatal lung disease characterized by inflammation and arrest of alveolarization. Its common sequela, pulmonary hypertension (PH), presents with elevated pulmonary vascular resistance associated with remodeling of the pulmonary arterioles. Despite notable advancements in neonatal medicine, there is a severe lack of curative treatments to help manage the progressive nature of these diseases. Numerous studies in preclinical models of BPD and PH have demonstrated that therapies based on mesenchymal stem/stromal cells (MSCs) can resolve pulmonary inflammation and ameliorate the severity of disease. Recent evidence suggests that novel, cell-free approaches based on MSC-derived exosomes (MEx) might represent a compelling therapeutic alternative offering major advantages over treatments based on MSC transplantation. Here, we will discuss the development of MSC-based therapies, stressing the centrality of paracrine action as the actual vector of MSC therapeutic functionality, focusing on MEx. We will briefly present our current understanding of the biogenesis and secretion of MEx, and discuss potential mechanisms by which they afford such beneficial effects, including immunomodulation and restoration of homeostasis in diseased states. We will also review ongoing clinical trials using MSCs as treatment for BPD that pave the way for bringing cell-free, MEx-based therapeutics from the bench to the NICU setting.
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Affiliation(s)
- Janette K. Burgess
- The University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands
| | - Irene H. Heijink
- The University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands
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Reza-Zaldivar EE, Hernández-Sapiéns MA, Gutiérrez-Mercado YK, Sandoval-Ávila S, Gomez-Pinedo U, Márquez-Aguirre AL, Vázquez-Méndez E, Padilla-Camberos E, Canales-Aguirre AA. Mesenchymal stem cell-derived exosomes promote neurogenesis and cognitive function recovery in a mouse model of Alzheimer's disease. Neural Regen Res 2019; 14:1626-1634. [PMID: 31089063 PMCID: PMC6557105 DOI: 10.4103/1673-5374.255978] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Studies have shown that mesenchymal stem cell-derived exosomes can enhance neural plasticity and improve cognitive impairment. The purpose of this study was to investigate the effects of mesenchymal stem cell-derived exosomes on neurogenesis and cognitive capacity in a mouse model of Alzheimer’s disease. Alzheimer’s disease mouse models were established by injection of beta amyloid 1−42 aggregates into dentate gyrus bilaterally. Morris water maze and novel object recognition tests were performed to evaluate mouse cognitive deficits at 14 and 28 days after administration. Afterwards, neurogenesis in the subventricular zone was determined by immunofluorescence using doublecortin and PSA-NCAM antibodies. Results showed that mesenchymal stem cells-derived exosomes stimulated neurogenesis in the subventricular zone and alleviated beta amyloid 1−42-induced cognitive impairment, and these effects are similar to those shown in the mesenchymal stem cells. These findings provide evidence to validate the possibility of developing cell-free therapeutic strategies for Alzheimer’s disease. All procedures and experiments were approved by Institutional Animal Care and Use Committee (CICUAL) (approval No. CICUAL 2016-011) on April 25, 2016.
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Affiliation(s)
- Edwin E Reza-Zaldivar
- Unidad de Evaluación Preclínica, Unidad de Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Mexico
| | - Mercedes A Hernández-Sapiéns
- Unidad de Evaluación Preclínica, Unidad de Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Mexico
| | - Yanet K Gutiérrez-Mercado
- Unidad de Evaluación Preclínica, Unidad de Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Mexico
| | - Sergio Sandoval-Ávila
- Unidad de Evaluación Preclínica, Unidad de Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Mexico
| | - Ulises Gomez-Pinedo
- Regenerative Medicine Unit, Neuroscience Institute, Department of Neurosurgery and Neurology, IdISSC Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
| | - Ana L Márquez-Aguirre
- Unidad de Evaluación Preclínica, Unidad de Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Mexico
| | - Estefanía Vázquez-Méndez
- Unidad de Evaluación Preclínica, Unidad de Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Mexico
| | - Eduardo Padilla-Camberos
- Unidad de Evaluación Preclínica, Unidad de Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Mexico
| | - Alejandro A Canales-Aguirre
- Unidad de Evaluación Preclínica, Unidad de Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Mexico
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Bruschettini M, Romantsik O, Moreira A, Ley D, Thébaud B. Stem cell-based interventions for the prevention of morbidity and mortality following hypoxic-ischaemic encephalopathy in newborn infants. Hippokratia 2018. [DOI: 10.1002/14651858.cd013202] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Matteo Bruschettini
- Lund University, Skåne University Hospital; Department of Paediatrics; Lund Sweden
- Skåne University Hospital; Cochrane Sweden; Wigerthuset, Remissgatan 4, first floor room 11-221 Lund Sweden 22185
| | - Olga Romantsik
- Lund University, Skåne University Hospital; Department of Paediatrics; Lund Sweden
| | - Alvaro Moreira
- University of Texas Health Science Center at San Antonio; Pediatrics, Division of Neonatology; San Antonio Texas USA
| | - David Ley
- Lund University, Skåne University Hospital; Department of Paediatrics; Lund Sweden
| | - Bernard Thébaud
- Children's Hospital of Eastern Ontario; Department of Pediatrics; Ottawa ON Canada
- Ottawa Hospital Research Institute, Sprott Center for Stem Cell Research; Ottawa Canada
- University of Ottawa; Department of Cellular and Molecular Medicine; Ottawa Canada
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35
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Romantsik O, Bruschettini M, Moreira A, Thébaud B, Ley D. Stem cell-based interventions for the prevention and treatment of germinal matrix-intraventricular haemorrhage in preterm infants. Hippokratia 2018. [DOI: 10.1002/14651858.cd013201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Olga Romantsik
- Lund University, Skåne University Hospital; Department of Paediatrics; Lund Sweden
| | - Matteo Bruschettini
- Lund University, Skåne University Hospital; Department of Paediatrics; Lund Sweden
- Skåne University Hospital; Cochrane Sweden; Wigerthuset, Remissgatan 4, first floor room 11-221 Lund Sweden 22185
| | - Alvaro Moreira
- University of Texas Health Science Center at San Antonio; Pediatrics, Division of Neonatology; San Antonio Texas USA
| | - Bernard Thébaud
- Children's Hospital of Eastern Ontario; Department of Pediatrics; Ottawa ON Canada
- Ottawa Hospital Research Institute, Sprott Center for Stem Cell Research; Ottawa Canada
- University of Ottawa; Department of Cellular and Molecular Medicine; Ottawa Canada
| | - David Ley
- Lund University, Skåne University Hospital; Department of Paediatrics; Lund Sweden
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Reza-Zaldivar EE, Hernández-Sapiéns MA, Minjarez B, Gutiérrez-Mercado YK, Márquez-Aguirre AL, Canales-Aguirre AA. Potential Effects of MSC-Derived Exosomes in Neuroplasticity in Alzheimer's Disease. Front Cell Neurosci 2018; 12:317. [PMID: 30319358 PMCID: PMC6165870 DOI: 10.3389/fncel.2018.00317] [Citation(s) in RCA: 123] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 08/30/2018] [Indexed: 12/23/2022] Open
Abstract
Alzheimer’s disease (AD) is the most common type of dementia affecting regions of the central nervous system that exhibit synaptic plasticity and are involved in higher brain functions such as learning and memory. AD is characterized by progressive cognitive dysfunction, memory loss and behavioral disturbances of synaptic plasticity and energy metabolism. Cell therapy has emerged as an alternative treatment of AD. The use of adult stem cells, such as neural stem cells and Mesenchymal Stem Cells (MSCs) from bone marrow and adipose tissue, have the potential to decrease cognitive deficits, possibly by reducing neuronal loss through blocking apoptosis, increasing neurogenesis, synaptogenesis and angiogenesis. These processes are mediated primarily by the secretion of many growth factors, anti-inflammatory proteins, membrane receptors, microRNAs (miRNA) and exosomes. Exosomes encapsulate and transfer several functional molecules like proteins, lipids and regulatory RNA which can modify cell metabolism. In the proteomic characterization of the content of MSC-derived exosomes, more than 730 proteins have been identified, some of which are specific cell type markers and others are involved in the regulation of binding and fusion of exosomes with adjacent cells. Furthermore, some factors were found that promote the recruitment, proliferation and differentiation of other cells like neural stem cells. Moreover, within exosomal cargo, a wide range of miRNAs were found, which can control functions related to neural remodeling as well as angiogenic and neurogenic processes. Taking this into consideration, the use of exosomes could be part of a strategy to promote neuroplasticity, improve cognitive impairment and neural replacement in AD. In this review, we describe how exosomes are involved in AD pathology and discuss the therapeutic potential of MSC-derived exosomes mediated by miRNA and protein cargo.
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Affiliation(s)
- Edwin E Reza-Zaldivar
- Unidad de Evaluación Preclínica, Biotecnología Médica y Farmacéutica, CONACYT Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara, Mexico
| | - Mercedes A Hernández-Sapiéns
- Unidad de Evaluación Preclínica, Biotecnología Médica y Farmacéutica, CONACYT Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara, Mexico
| | - Benito Minjarez
- Centro Universitario de Ciencias Biológicas y Agropecuarias (CUCBA), Universidad de Guadalajara, Guadalajara, Mexico
| | - Yanet K Gutiérrez-Mercado
- Unidad de Evaluación Preclínica, Biotecnología Médica y Farmacéutica, CONACYT Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara, Mexico
| | - Ana L Márquez-Aguirre
- Unidad de Evaluación Preclínica, Biotecnología Médica y Farmacéutica, CONACYT Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara, Mexico
| | - Alejandro A Canales-Aguirre
- Unidad de Evaluación Preclínica, Biotecnología Médica y Farmacéutica, CONACYT Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara, Mexico.,Profesor del programa de Maestría en Ciencias de la Salud Ambiental, Centro Universitario de Ciencias Biológicas y Agropecuarias (CUCBA), Universidad de Guadalajara, Guadalajara, Mexico
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Willis GR, Fernandez-Gonzalez A, Reis M, Mitsialis SA, Kourembanas S. Macrophage Immunomodulation: The Gatekeeper for Mesenchymal Stem Cell Derived-Exosomes in Pulmonary Arterial Hypertension? Int J Mol Sci 2018; 19:ijms19092534. [PMID: 30150544 PMCID: PMC6164282 DOI: 10.3390/ijms19092534] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 08/21/2018] [Accepted: 08/22/2018] [Indexed: 12/13/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by remodeling of the pulmonary arteries, increased pulmonary infiltrates, loss of vascular cross-sectional area, and elevated pulmonary vascular resistance. Despite recent advances in the management of PAH, there is a pressing need for the development of new tools to effectively treat and reduce the risk of further complications. Dysregulated immunity underlies the development of PAH, and macrophages orchestrate both the initiation and resolution of pulmonary inflammation, thus, manipulation of lung macrophage function represents an attractive target for emerging immunomodulatory therapies, including cell-based approaches. Indeed, mesenchymal stem cell (MSC)-based therapies have shown promise, effectively modulating the macrophage fulcrum to favor an anti-inflammatory, pro-resolving phenotype, which is associated with both histological and functional benefits in preclinical models of pulmonary hypertension (PH). The complex interplay between immune system homeostasis and MSCs remains incompletely understood. Here, we highlight the importance of macrophage function in models of PH and summarize the development of MSC-based therapies, focusing on the significance of MSC exosomes (MEx) and the immunomodulatory and homeostatic mechanisms by which such therapies may afford their beneficial effects.
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Affiliation(s)
- Gareth R Willis
- Division of Newborn Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
| | - Angeles Fernandez-Gonzalez
- Division of Newborn Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
| | - Monica Reis
- Division of Newborn Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
| | - S Alex Mitsialis
- Division of Newborn Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
| | - Stella Kourembanas
- Division of Newborn Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
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Safety of Autologous Cord Blood Cells for Preterms: A Descriptive Study. Stem Cells Int 2018; 2018:5268057. [PMID: 30186329 PMCID: PMC6114055 DOI: 10.1155/2018/5268057] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 06/26/2018] [Accepted: 07/19/2018] [Indexed: 12/18/2022] Open
Abstract
Background Preterm birth complications are one of the leading causes of death among children under 5 years of age. Despite advances in medical care, many survivors face a lifetime of disability, including mental and physical retardation, and chronic lung disease. More recently, both allogenic and autogenic cord blood cells have been applied in the treatment of neonatal conditions such as hypoxic-ischemic encephalopathy (HIE) and bronchopulmonary dysplasia (BPD). Objective To assess the safety of autologous, volume- and red blood cell- (RBC-) reduced, noncryopreserved umbilical cord blood (UCB) cell infusion to preterm infants. Method This study was a phase I, open-label, single-arm, single-center trial to evaluate the safety of autologous, volume- and RBC-reduced, noncryopreserved UCB cell (5 × 107cells/kg) infusion for preterm infants <37 weeks gestational age. UCB cell characteristics, pre- and postinfusion vital signs, and laboratory investigations were recorded. Clinical data including mortality rates and preterm complications were recorded. Results After processing, (22.67 ± 4.05) ml UCB cells in volume, (2.67 ± 2.00) × 108 cells in number, with (22.67 ± 4.05) × 106 CD34+, (3.72 ± 3.25) × 105 colony forming cells (CFU-GM), and (99.7 ± 0.17%) vitality were infused to 15 preterm infants within 8 hours after birth. No adverse effects were noticed during treatment. All fifteen patients who received UCB infusion survived. The duration of hospitalization ranged from 4 to 65 (30 ± 23.6) days. Regarding preterm complications, no BPD, necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP) was observed. There were 1/15 (7%) infant with intraventricular hemorrhage (IVH), 5/15 (33.3%) infants with ventilation-associated pneumonia, and 10/15 (66.67%) with anemia, respectively. Conclusions Collection, preparation, and infusion of fresh autologous UCB cells to preterm infants is feasible and safe. Adequately powered randomized controlled studies are needed.
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Nair J, Kumar VHS. Current and Emerging Therapies in the Management of Hypoxic Ischemic Encephalopathy in Neonates. CHILDREN (BASEL, SWITZERLAND) 2018; 5:E99. [PMID: 30029531 PMCID: PMC6069156 DOI: 10.3390/children5070099] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Revised: 07/09/2018] [Accepted: 07/16/2018] [Indexed: 01/01/2023]
Abstract
Neonatal hypoxic ischemic encephalopathy (HIE) presents a significant clinical burden with its high mortality and morbidity rates globally. Therapeutic hypothermia (TH) is now standard of care for infants with moderate to severe HIE, but has not definitively changed outcomes in severe HIE. In this review, we discuss newer promising markers that may help the clinician identify severity of HIE. Therapies that are beneficial and agents that hold promise for neuroprotection are described, both for use either alone or as adjuncts to TH. These include endogenous pathway modifiers such as erythropoietin and analogues, melatonin, and remote ischemic post conditioning. Stem cells have therapeutic potential in this condition, as in many other neonatal conditions. Of the agents listed, only erythropoietin and analogues are currently being evaluated in large randomized controlled trials (RCTs). Exogenous therapies such as argon and xenon, allopurinol, monosialogangliosides, and magnesium sulfate continue to be investigated. The recognition of tertiary mechanisms of brain damage has opened up new research into therapies not only to attenuate brain damage but also to promote cell repair and regeneration in a developmentally disorganized brain long after the perinatal insult. These alternative modalities may be especially important in mild HIE and in areas of the world where there is limited access to expensive hypothermia equipment and services.
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Affiliation(s)
- Jayasree Nair
- Division of Neonatology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA.
| | - Vasantha H S Kumar
- Division of Neonatology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA.
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Abstract
With the advancements in antenatal steroid therapies and surfactant replacement, current clinical practices in neonatal intensive care units allow the survival of infants at very low gestational age. Despite these advances, there continues to be significant morbidity associated with extreme preterm birth that includes both short-term and long-term cardiorespiratory impairment. With no effective single therapy in preventing or treating developmental lung injuries, the need for new tools to treat and reduce risk of complications associated with extreme preterm birth is urgent. Stem cell-based therapies, in particular therapies utilizing mesenchymal stem (stromal) cells (MSCs), have shown promise in a number of animal models of lung pathologies relevant to neonatology. Recent studies in this field have consolidated the concept that the therapeutic mechanism of MSC action is paracrine, and this led to wide acceptance of the concept that the delivery of the MSC secretome rather than live cells may provide an alternative therapeutic approach for many complex diseases. Here, we summarize the significance and application of cell-free based therapies in preclinical models of neonatal lung injury. We emphasize the development of extracellular vesicle (EV)-based therapeutics and focus on the challenges that remain to be addressed before their application to clinical practice.
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Twilhaar ES, Wade RM, de Kieviet JF, van Goudoever JB, van Elburg RM, Oosterlaan J. Cognitive Outcomes of Children Born Extremely or Very Preterm Since the 1990s and Associated Risk Factors: A Meta-analysis and Meta-regression. JAMA Pediatr 2018; 172:361-367. [PMID: 29459939 PMCID: PMC5875339 DOI: 10.1001/jamapediatrics.2017.5323] [Citation(s) in RCA: 367] [Impact Index Per Article: 52.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 11/22/2017] [Indexed: 11/14/2022]
Abstract
Importance Despite apparent progress in perinatal care, children born extremely or very preterm (EP/VP) remain at high risk for cognitive deficits. Insight into factors contributing to cognitive outcome is key to improve outcomes after EP/VP birth. Objective To examine the cognitive abilities of children of EP/VP birth (EP/VP children) and the role of perinatal and demographic risk factors. Data Sources PubMed, Web of Science, and PsycINFO were searched without language restriction (last search March 2, 2017). Key search terms included preterm, low birth weight, and intelligence. Study Selection Peer-reviewed studies reporting intelligence scores of EP/VP children (<32 weeks of gestation) and full-term controls at age 5 years or older, born in the antenatal corticosteroids and surfactant era, were included. A total of 268 studies met selection criteria, of which 71 covered unique cohorts. Data Extraction and Synthesis MOOSE guidelines were followed. Data were independently extracted by 2 researchers. Standardized mean differences in intelligence per study were pooled using random-effects meta-analysis. Heterogeneity in effect size across studies was studied using multivariate, random-effects meta-regression analysis. Main Outcomes and Measures Primary outcome was intelligence. Covariates included gestational age, birth weight, birth year, age at assessment, sex, race/ethnicity, socioeconomic status, small for gestational age, intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis, sepsis, and postnatal corticosteroid use. Results The 71 included studies comprised 7752 EP/VP children and 5155 controls. Median gestational age was 28.5 weeks (interquartile range [IQR], 2.4 weeks) and the mean age at assessment ranged from 5.0 to 20.1 years. The median proportion of males was 50.0% (IQR, 8.7%). Preterm children had a 0.86-SD lower IQ compared with controls (95% CI, -0.94 to -0.78, P < .001). Results were heterogeneous across studies (I2 = 74.13; P < .001). This heterogeneity could not be explained by birth year of the cohort. Multivariate meta-regression analysis with backward elimination revealed that BPD explained 65% of the variance in intelligence across studies, with each percent increase in BPD rate across studies associated with a 0.01-SD decrease in IQ (0.15 IQ points) (P < .001). Conclusions and Relevance Extremely or very preterm children born in the antenatal corticosteroids and surfactant era show large deficits in intelligence. No improvement in cognitive outcome was observed between 1990 and 2008. These findings emphasize that improving outcomes after EP/VP birth remains a major challenge. Bronchopulmonary dysplasia was found to be a crucial factor for cognitive outcome. Lowering the high incidence of BPD may be key to improving long-term outcomes after EP/VP birth.
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Affiliation(s)
- E. Sabrina Twilhaar
- Clinical Neuropsychology Section, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Rebecca M. Wade
- Clinical Neuropsychology Section, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Jorrit F. de Kieviet
- Clinical Neuropsychology Section, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Johannes B. van Goudoever
- Department of Pediatrics, Emma Children’s Hospital, Academic Medical Center, Amsterdam, the Netherlands
- Department of Pediatrics, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
| | - Ruurd M. van Elburg
- Department of Pediatrics, Emma Children’s Hospital, Academic Medical Center, Amsterdam, the Netherlands
- Nutricia Research, Utrecht, the Netherlands
| | - Jaap Oosterlaan
- Clinical Neuropsychology Section, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- Department of Pediatrics, Emma Children’s Hospital, Academic Medical Center, Amsterdam, the Netherlands
- Department of Pediatrics, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
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"Good things come in small packages": application of exosome-based therapeutics in neonatal lung injury. Pediatr Res 2018; 83:298-307. [PMID: 28985201 PMCID: PMC5876073 DOI: 10.1038/pr.2017.256] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 09/29/2017] [Indexed: 02/07/2023]
Abstract
Infants born at very low gestational age contribute disproportionately to neonatal morbidity and mortality. Advancements in antenatal steroid therapies and surfactant replacement have favored the survival of infants with ever-more immature lungs. Despite such advances in medical care, cardiopulmonary and neurological impairment prevail in constituting the major adverse outcomes for neonatal intensive care unit survivors. With no single effective therapy for either the prevention or treatment of such neonatal disorders, the need for new tools to treat and reduce risk of further complications associated with extreme preterm birth is urgent. Mesenchymal stem/stromal cell (MSC)-based approaches have shown promise in numerous experimental models of lung injury relevant to neonatology. Recent studies have highlighted that the therapeutic potential of MSCs is harnessed in their secretome, and that the therapeutic vector therein is represented by the exosomes released by MSCs. In this review, we summarize the development and significance of stem cell-based therapies for neonatal diseases, focusing on preclinical models of neonatal lung injury. We emphasize the development of MSC exosome-based therapeutics and comment on the challenges in bringing these promising interventions to clinic.
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Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders. Pediatr Res 2018; 83:214-222. [PMID: 28972960 DOI: 10.1038/pr.2017.249] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 09/21/2017] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cell (MSC) transplantation represents the next breakthrough in the treatment of currently intractable and devastating neonatal disorders with complex multifactorial etiologies, including bronchopulmonary dysplasia, hypoxic ischemic encephalopathy, and intraventricular hemorrhage. Absent engraftment and direct differentiation of transplanted MSCs, and the "hit-and-run" therapeutic effects of these MSCs suggest that their pleiotropic protection might be attributable to paracrine activity via the secretion of various biologic factors rather than to regenerative activity. The transplanted MSCs, therefore, exert their therapeutic effects not by acting as "stem cells," but rather by acting as "paracrine factors factory." The MSCs sense the microenvironment of the injury site and secrete various paracrine factors that serve several reparative functions, including antiapoptotic, anti-inflammatory, antioxidative, antifibrotic, and/or antibacterial effects in response to environmental cues to enhance regeneration of the damaged tissue. Therefore, the therapeutic efficacy of MSCs might be dependent on their paracrine potency. In this review, we focus on recent investigations that elucidate the specifically regulated paracrine mechanisms of MSCs by injury type and discuss potential strategies to enhance paracrine potency, and thus therapeutic efficacy, of transplanted MSCs, including determining the appropriate source and preconditioning strategy for MSCs and the route and timing of their administration.
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Archambault J, Moreira A, McDaniel D, Winter L, Sun L, Hornsby P. Therapeutic potential of mesenchymal stromal cells for hypoxic ischemic encephalopathy: A systematic review and meta-analysis of preclinical studies. PLoS One 2017; 12:e0189895. [PMID: 29261798 PMCID: PMC5736208 DOI: 10.1371/journal.pone.0189895] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 12/04/2017] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Neonatal hypoxic ischemic encephalopathy (HIE) is a devastating neurologic condition with high mortality rates and long-term complications for surviving infants. Mesenchymal stem/stromal cells (MSCs) have emerged as novel therapeutic agents with promising results in experimental studies of HIE. The purpose of this study is to (a) methodically review the current preclinical literature describing MSC therapy in animal models of HIE, (b) quantify the effect size in regards to functional neurologic outcome, and (c) identify research gaps/limitations that should be addressed prior to future preclinical and clinical studies. METHODS Adhering to the Systematic Review Protocol for Animal Intervention Studies, a systematic search of English articles was performed. Eligible studies were identified and data regarding study characteristics and outcome measures was extracted. After quality assessment, meta-analysis and meta-regression were performed to generate random effect size using standardized mean difference (SMD). Funnel plots and Egger's tests were utilized to evaluate for the presence of publication bias. RESULTS A total of 19 studies met inclusion in the current systematic review. Meta-analysis revealed that MSCs have a significant positive effect on neurobehavioral outcome following HIE injury. Sensorimotor function was improved by 2.25 SMD (95% CI; 2.04-2.46) in cylinder rearing and 2.97 SMD (95% CI; 2.56-3.38) in rotarod. Likewise, cognitive function was improved by 2.76 SMD (95% CI; 2.53-2.98) on the water maze and 2.97 SMD (95% CI; 2.58-3.35) in object recognition. Stratification demonstrated an increased effect size depending on various study characteristics. CONCLUSIONS Overall, these results suggest a promising role for MSCs in preclinical studies of HIE. MSC treatment demonstrates improved functional outcomes that are encouraging for future translational studies. While risk of bias and heterogeneity limited the strength of our meta-analysis, our results are consistent with those seen in this field of research.
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Affiliation(s)
- Jamie Archambault
- Department of Pediatrics, Division of Neonatology, University of Texas Health-San Antonio, San Antonio, Texas, United States of America
| | - Alvaro Moreira
- Department of Pediatrics, Division of Neonatology, University of Texas Health-San Antonio, San Antonio, Texas, United States of America
| | - Dawn McDaniel
- Department of Pediatrics, Division of Neonatology, University of Texas Health-San Antonio, San Antonio, Texas, United States of America
| | - Lauryn Winter
- Department of Pediatrics, Division of Neonatology, University of Texas Health-San Antonio, San Antonio, Texas, United States of America
| | - LuZhe Sun
- Department of Cell Systems and Anatomy, University of Texas Health-San Antonio, San Antonio, Texas, United States of America
| | - Peter Hornsby
- Department of Cellular and Integrative Physiology, Barshop Institute for Longevity and Aging Studies, University of Texas Health-San Antonio, San Antonio, Texas, United States of America
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45
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Willis GR, Kourembanas S, Mitsialis SA. Toward Exosome-Based Therapeutics: Isolation, Heterogeneity, and Fit-for-Purpose Potency. Front Cardiovasc Med 2017; 4:63. [PMID: 29062835 PMCID: PMC5640880 DOI: 10.3389/fcvm.2017.00063] [Citation(s) in RCA: 190] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 09/25/2017] [Indexed: 12/11/2022] Open
Abstract
Exosomes are defined as submicron (30-150 nm), lipid bilayer-enclosed extracellular vesicles (EVs), specifically generated by the late endosomal compartment through fusion of multivesicular bodies with the plasma membrane. Produced by almost all cells, exosomes were originally considered to represent just a mechanism for jettisoning unwanted cellular moieties. Although this may be a major function in most cells, evolution has recruited the endosomal membrane-sorting pathway to duties beyond mere garbage disposal, one of the most notable examples being its cooption by retroviruses for the generation of Trojan virions. It is, therefore, tempting to speculate that certain cell types have evolved an exosome subclass active in intracellular communication. We term this EV subclass "signalosomes" and define them as exosomes that are produced by the "signaling" cells upon specific physiological or environmental cues and harbor cargo capable of modulating the programming of recipient cells. Our recent studies have established that signalosomes released by mesenchymal stem/stromal cells (MSCs) represent the main vector of MSC immunomodulation and therapeutic action in animal models of lung disease. The efficacy of MSC-exosome treatments in a number of preclinical models of cardiovascular and pulmonary disease supports the promise of application of exosome-based therapeutics across a wide range of pathologies within the near future. However, the full realization of exosome therapeutic potential has been hampered by the absence of standardization in EV isolation, and procedures for purification of signalosomes from the main exosome population. This is mainly due to immature methodologies for exosome isolation and characterization and our incomplete understanding of the specific characteristics and molecular composition of signalosomes. In addition, difficulties in defining metrics for potency of exosome preparations and the challenges of industrial scale-up and good manufacturing practice compliance have complicated smooth and timely transition to clinical development. In this manuscript, we focus on cell culture conditions, exosome harvesting, dosage, and exosome potency, providing some empirical guidance and perspectives on the challenges in bringing exosome-based therapies to clinic.
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Affiliation(s)
- Gareth R Willis
- Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Boston, MA, United States.,Department of Pediatrics, Harvard Medical School, Boston, MA, United States
| | - Stella Kourembanas
- Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Boston, MA, United States.,Department of Pediatrics, Harvard Medical School, Boston, MA, United States
| | - S Alex Mitsialis
- Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Boston, MA, United States.,Department of Pediatrics, Harvard Medical School, Boston, MA, United States
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Laffey JG, Matthay MA. Fifty Years of Research in ARDS. Cell-based Therapy for Acute Respiratory Distress Syndrome. Biology and Potential Therapeutic Value. Am J Respir Crit Care Med 2017; 196:266-273. [PMID: 28306336 DOI: 10.1164/rccm.201701-0107cp] [Citation(s) in RCA: 177] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
On the basis of several preclinical studies, cell-based therapy has emerged as a potential new therapeutic for acute respiratory distress syndrome (ARDS). Of the various cell-based therapy options, mesenchymal stem/stromal cells (MSCs) from bone marrow, adipose tissue, and umbilical cord have the most experimental data to support their potential efficacy for lung injury from both infectious and noninfectious causes. Mechanistically, MSCs exert their beneficial effects by release of paracrine factors, microvesicles, and transfer of mitochondria, all of which have antiinflammatory and pro-resolving effects on injured lung endothelium and alveolar epithelium, including enhancing the resolution of pulmonary edema by up-regulating sodium-dependent alveolar fluid clearance. MSCs also have antimicrobial effects mediated by release of antimicrobial factors and by up-regulating monocyte/macrophage phagocytosis. Phase 2a clinical trials to establish safety in ARDS are in progress, and two phase 1 trials did not report any serious adverse events. Several issues need further study, including: determining the optimal methods for large-scale production, reconstitution of cryopreserved cells for clinical use, defining cell potency assays, and determining the therapeutic potential of conditioned media derived from MSCs. Because ARDS is a heterogeneous syndrome, targeting MSCs to patients with ARDS with a more hyperinflammatory endotype may further enhance their potential for efficacy.
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Affiliation(s)
- John G Laffey
- 1 Department of Anesthesia and.,2 Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada; and
| | - Michael A Matthay
- 3 Department of Medicine and.,4 Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California
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Collins JJP, Tibboel D, de Kleer IM, Reiss IKM, Rottier RJ. The Future of Bronchopulmonary Dysplasia: Emerging Pathophysiological Concepts and Potential New Avenues of Treatment. Front Med (Lausanne) 2017; 4:61. [PMID: 28589122 PMCID: PMC5439211 DOI: 10.3389/fmed.2017.00061] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 05/02/2017] [Indexed: 12/13/2022] Open
Abstract
Yearly more than 15 million babies are born premature (<37 weeks gestational age), accounting for more than 1 in 10 births worldwide. Lung injury caused by maternal chorioamnionitis or preeclampsia, postnatal ventilation, hyperoxia, or inflammation can lead to the development of bronchopulmonary dysplasia (BPD), one of the most common adverse outcomes in these preterm neonates. BPD patients have an arrest in alveolar and microvascular development and more frequently develop asthma and early-onset emphysema as they age. Understanding how the alveoli develop, and repair, and regenerate after injury is critical for the development of therapies, as unfortunately there is still no cure for BPD. In this review, we aim to provide an overview of emerging new concepts in the understanding of perinatal lung development and injury from a molecular and cellular point of view and how this is paving the way for new therapeutic options to prevent or treat BPD, as well as a reflection on current treatment procedures.
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Affiliation(s)
- Jennifer J P Collins
- Department of Pediatric Surgery, Sophia Children's Hospital, Erasmus University Medical Centre, Rotterdam, Netherlands
| | - Dick Tibboel
- Department of Pediatric Surgery, Sophia Children's Hospital, Erasmus University Medical Centre, Rotterdam, Netherlands
| | - Ismé M de Kleer
- Division of Pediatric Pulmonology, Department of Pediatrics, Sophia Children's Hospital, Erasmus University Medical Centre, Rotterdam, Netherlands
| | - Irwin K M Reiss
- Division of Neonatology, Department of Pediatrics, Sophia Children's Hospital, Erasmus University Medical Centre, Rotterdam, Netherlands
| | - Robbert J Rottier
- Department of Pediatric Surgery, Sophia Children's Hospital, Erasmus University Medical Centre, Rotterdam, Netherlands
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Collino F, Pomatto M, Bruno S, Lindoso RS, Tapparo M, Sicheng W, Quesenberry P, Camussi G. Exosome and Microvesicle-Enriched Fractions Isolated from Mesenchymal Stem Cells by Gradient Separation Showed Different Molecular Signatures and Functions on Renal Tubular Epithelial Cells. Stem Cell Rev Rep 2017; 13:226-243. [PMID: 28070858 PMCID: PMC5380712 DOI: 10.1007/s12015-016-9713-1] [Citation(s) in RCA: 129] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Several studies have suggested that extracellular vesicles (EVs) released from mesenchymal stem cells (MSCs) may mediate MSC paracrine action on kidney regeneration. This activity has been, at least in part, ascribed to the transfer of proteins/transcription factors and different RNA species. Information on the RNA/protein content of different MSC EV subpopulations and the correlation with their biological activity is currently incomplete. The aim of this study was to evaluate the molecular composition and the functional properties on renal target cells of MSC EV sub-populations separated by gradient floatation. The results demonstrated heterogeneity in quantity and composition of MSC EVs. Two peaks of diameter were observed (90-110 and 170-190 nm). The distribution of exosomal markers and miRNAs evaluated in the twelve gradient fractions showed an enrichment in fractions with a flotation density of 1.08-1.14 g/mL. Based on this observation, we evaluated the biological activity on renal cell proliferation and apoptosis resistance of low (CF1), medium (CF2) and high (CF3) floatation density fractions. EVs derived from all fractions, were internalized by renal cells, CF1 and CF2 but not CF3 fraction stimulated significant cell proliferation. CF2 also inhibited apoptosis on renal tubular cells submitted to ischemia-reperfusion injury. Comparative miRNomic and proteomic profiles reveal a cluster of miRNAs and proteins common to all three fractions and an enrichment of selected molecules related to renal regeneration in CF2 fraction. In conclusion, the CF2 fraction enriched in exosomal markers was the most active on renal tubular cell proliferation and protection from apoptosis.
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Affiliation(s)
- Federica Collino
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- Department of Medical Sciences and 2i3T, University of Torino, Torino, Italy
| | - Margherita Pomatto
- Department of Medical Sciences and 2i3T, University of Torino, Torino, Italy
| | - Stefania Bruno
- Department of Molecular Biotechnology and Healthy Science, Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Rafael Soares Lindoso
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Marta Tapparo
- Department of Medical Sciences and 2i3T, University of Torino, Torino, Italy
| | - Wen Sicheng
- Division of Hematology/Oncology, Rhode Island Hospital, Brown University, Providence, RI, USA
| | - Peter Quesenberry
- Division of Hematology/Oncology, Rhode Island Hospital, Brown University, Providence, RI, USA
| | - Giovanni Camussi
- Department of Medical Sciences and 2i3T, University of Torino, Torino, Italy.
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Mills DR, Mao Q, Chu S, Falcon Girard K, Kraus M, Padbury JF, De Paepe ME. Effects of human umbilical cord blood mononuclear cells on respiratory system mechanics in a murine model of neonatal lung injury. Exp Lung Res 2017; 43:66-81. [PMID: 28353351 DOI: 10.1080/01902148.2017.1300713] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Mononuclear cells (MNCs) have well-documented beneficial effects in a wide range of adult pulmonary diseases. The effects of human umbilical cord blood-derived MNCs on neonatal lung injury, highly relevant for potential autologous application in preterm newborns at risk for bronchopulmonary dysplasia (BPD), remain incompletely established. The aim of this study was to determine the long-term morphologic and functional effects of systemically delivered MNCs in a murine model of neonatal lung injury. MATERIALS AND METHODS MNCs from cryopreserved cord blood (1 × 106 cells per pup) were given intravenously to newborn mice exposed to 90% O2 from birth; controls received cord blood total nucleated cells (TNCs) or granular cells, or equal volume vehicle buffer (sham controls). In order to avoid immune rejection, we used SCID mice as recipients. Lung mechanics (flexiVent™), engraftment, growth, and alveolarization were evaluated eight weeks postinfusion. RESULTS Systemic MNC administration to hyperoxia-exposed newborn mice resulted in significant attenuation of methacholine-induced airway hyperreactivity, leading to reduction of central airway resistance to normoxic levels. These bronchial effects were associated with mild improvement of alveolarization, lung compliance, and elastance. TNCs had no effects on alveolar remodeling and were associated with worsened methacholine-induced bronchial hyperreactivity. Granular cell administration resulted in a marked morphologic and functional emphysematous phenotype, associated with high mortality. Pulmonary donor cell engraftment was sporadic in all groups. CONCLUSIONS These results suggest that cord blood MNCs may have a cell type-specific role in therapy of pulmonary conditions characterized by increased airway resistance, such as BPD and asthma. Future studies need to determine the active MNC subtype(s), their mechanisms of action, and optimal purification methods to minimize granular cell contamination.
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Affiliation(s)
- David R Mills
- a Department of Pathology , Women and Infants Hospital , Providence , Rhode Island , USA
| | - Quanfu Mao
- a Department of Pathology , Women and Infants Hospital , Providence , Rhode Island , USA.,b Department of Pathology and Laboratory Medicine , Alpert Medical School of Brown University , Providence , Rhode Island , USA
| | - Sharon Chu
- a Department of Pathology , Women and Infants Hospital , Providence , Rhode Island , USA.,b Department of Pathology and Laboratory Medicine , Alpert Medical School of Brown University , Providence , Rhode Island , USA
| | | | - Morey Kraus
- c ViaCord LLC, a Perkin Elmer Company , Cambridge , Massachusetts , USA
| | - James F Padbury
- d Department of Pediatrics , Women and Infants Hospital , Providence , Rhode Island , USA.,e Department of Pediatrics , Alpert Medical School of Brown University , Providence , Rhode Island , USA
| | - Monique E De Paepe
- a Department of Pathology , Women and Infants Hospital , Providence , Rhode Island , USA.,b Department of Pathology and Laboratory Medicine , Alpert Medical School of Brown University , Providence , Rhode Island , USA
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50
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Drommelschmidt K, Serdar M, Bendix I, Herz J, Bertling F, Prager S, Keller M, Ludwig AK, Duhan V, Radtke S, de Miroschedji K, Horn PA, van de Looij Y, Giebel B, Felderhoff-Müser U. Mesenchymal stem cell-derived extracellular vesicles ameliorate inflammation-induced preterm brain injury. Brain Behav Immun 2017; 60:220-232. [PMID: 27847282 DOI: 10.1016/j.bbi.2016.11.011] [Citation(s) in RCA: 218] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Revised: 11/04/2016] [Accepted: 11/12/2016] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVE Preterm brain injury is a major cause of disability in later life, and may result in motor, cognitive and behavioural impairment for which no treatment is currently available. The aetiology is considered as multifactorial, and one underlying key player is inflammation leading to white and grey matter injury. Extracellular vesicles secreted by mesenchymal stem/stromal cells (MSC-EVs) have shown therapeutic potential in regenerative medicine. Here, we investigated the effects of MSC-EV treatment on brain microstructure and maturation, inflammatory processes and long-time outcome in a rodent model of inflammation-induced brain injury. METHODS 3-Day-old Wistar rats (P3) were intraperitoneally injected with 0.25mg/kg lipopolysaccharide or saline and treated with two repetitive doses of 1×108 cell equivalents of MSC-EVs per kg bodyweight. Cellular degeneration and reactive gliosis at P5 and myelination at P11 were evaluated by immunohistochemistry and western blot. Long-term cognitive and motor function was assessed by behavioural testing. Diffusion tensor imaging at P125 evaluated long-term microstructural white matter alterations. RESULTS MSC-EV treatment significantly ameliorated inflammation-induced neuronal cellular degeneration reduced microgliosis and prevented reactive astrogliosis. Short-term myelination deficits and long-term microstructural abnormalities of the white matter were restored by MSC-EV administration. Morphological effects of MSC-EV treatment resulted in improved long-lasting cognitive functions INTERPRETATION: MSC-EVs ameliorate inflammation-induced cellular damage in a rat model of preterm brain injury. MSC-EVs may serve as a novel therapeutic option by prevention of neuronal cell death, restoration of white matter microstructure, reduction of gliosis and long-term functional improvement.
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Affiliation(s)
- Karla Drommelschmidt
- Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Meray Serdar
- Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Ivo Bendix
- Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Josephine Herz
- Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Frederik Bertling
- Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Sebastian Prager
- Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Matthias Keller
- Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Anna-Kristin Ludwig
- Institute of Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Vikas Duhan
- Institute of Immunology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Stefan Radtke
- Institute of Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Clinical Research Division, Fred Hutchinson Cancer Research Centre, Seattle, WA 98109, USA
| | - Kyra de Miroschedji
- Institute of Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Peter A Horn
- Institute of Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Yohan van de Looij
- Division of Child Growth and Development, Department of Paediatrics, University of Geneva, Geneva, Switzerland; Laboratory of Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Bernd Giebel
- Institute of Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
| | - Ursula Felderhoff-Müser
- Department of Paediatrics I/Neonatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
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