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Maltais-Bilodeau C, Henckel E, Deguise MO, Lesage F, Cobey KD, Ahmadzai N, Skidmore B, Ferretti E, Thébaud B. Cell-based therapies in preclinical models of necrotizing enterocolitis: a systematic review and meta-analysis. Stem Cells Transl Med 2025; 14:szae102. [PMID: 40036304 PMCID: PMC11878585 DOI: 10.1093/stcltm/szae102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 12/18/2024] [Indexed: 03/06/2025] Open
Abstract
Necrotizing enterocolitis (NEC) remains an incurable gut complication of prematurity with significant morbidity and mortality. Cell therapies, including mesenchymal stromal cells (MSCs), may be a promising treatment given their anti-inflammatory and regenerative potential. We assessed the effect of MSCs and other cell therapies (not classified as MSCs) on incidence, severity, and mortality in preclinical models of NEC. Bibliographic and gray literature searches yielded 17 371 records with 107 full-text articles assessed and ultimately 16 studies were included. These studies featured only rodents NEC models via combination of hyperosmolar feeds, hypoxia, hypothermia, or lipopolysaccharides. Ten studies used interventions with MSCs. Only 2 met the minimal criteria to define MSCs proposed by the International Society for Cell & Gene Therapy (ISCT). The overall risk of bias was assessed as high partly due to paucity of data with important gaps in reporting, reinforcing the importance of rigorous research framework, appropriate cell-therapy and outcome reporting in preclinical research. A reduction in the incidence of NEC (odds ratio [OR] 0.32, 95% CI [0.17, 0.62]), severe NEC (OR 0.30, 95% CI [0.18, 0.50]), and mortality (OR 0.30, 95% CI [0.16, 0.55]) was noted with MSCs treatment, seemingly more pronounced for ISCT-defined (ISCT+) MSCs. Amniotic fluid stem cells, neural stem cells, and placenta stem cells also showed a reduction in these measures. Given their accessibility (ie, umbilical cord) and proven safety profile in extremely preterm infants, our analysis provides a foundation for considering MSCs as promising candidate that requires further evaluation for the treatment of NEC.
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Affiliation(s)
- Camille Maltais-Bilodeau
- Division of Neonatology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada
- Department of Obstetrics, Gynecology and Newborn Care, The Ottawa Hospital, General Campus, Ottawa, ON K1H 8L6, Canada
| | - Ewa Henckel
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm 171 77, Sweden
- Department of Neonatology, Karolinska University Hospital, Stockholm 171 77, Sweden
- Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Marc-Olivier Deguise
- Division of Neonatology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada
- Department of Obstetrics, Gynecology and Newborn Care, The Ottawa Hospital, General Campus, Ottawa, ON K1H 8L6, Canada
- Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Flore Lesage
- Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
| | - Kelly D Cobey
- Meta Research and Open Science Program, University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada
- School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Nadera Ahmadzai
- Independent Information Specialist, Ottawa, ON K1T 3Z2, Canada
| | - Becky Skidmore
- Independent Information Specialist, Ottawa, ON K1T 3Z2, Canada
| | - Emanuela Ferretti
- Division of Neonatology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada
- Department of Obstetrics, Gynecology and Newborn Care, The Ottawa Hospital, General Campus, Ottawa, ON K1H 8L6, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Bernard Thébaud
- Division of Neonatology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada
- Department of Obstetrics, Gynecology and Newborn Care, The Ottawa Hospital, General Campus, Ottawa, ON K1H 8L6, Canada
- Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
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2
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Yang J, Li D, Zhang M, Lin G, Hu S, Xu H. From the updated landscape of the emerging biologics for IBDs treatment to the new delivery systems. J Control Release 2023; 361:568-591. [PMID: 37572962 DOI: 10.1016/j.jconrel.2023.08.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/06/2023] [Accepted: 08/06/2023] [Indexed: 08/14/2023]
Abstract
Inflammatory bowel diseases (IBDs) treatments have shifted from small-molecular therapeutics to the oncoming biologics. The first-line biologics against the moderate-to-severe IBDs are mainly involved in antibodies against integrins, cytokines and cell adhesion molecules. Besides, other biologics including growth factors, antioxidative enzyme, anti-inflammatory peptides, nucleic acids, stem cells and probiotics have also been explored at preclinical or clinical studies. Biologics with variety of origins have their unique potentials in attenuating immune inflammation or gut mucosa healing. Great advances in use of biologics for IBDs treatments have been archived in recent years. But delivering issues for biologic have also been confronted due to their liable nature. In this review, we will focus on biologics for IBDs treatments in the recent publications; summarize the current landscapes of biologics and their promise to control disease progress. Alternatively, the confronted challenges for delivering biologics will also be analyzed. To combat these drawbacks, some new delivering strategies are provided: firstly, designing the functional materials with high affinity toward biologics; secondly, the delivering vehicle systems to encapsulate the liable biologics; thirdly, the topical adhering delivery systems as enema. To our knowledge, this review is the first study to summarize the updated usage of the oncoming biologics for IBDs, their confronted challenges in term of delivery and the potential combating strategies.
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Affiliation(s)
- Jiaojiao Yang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Dingwei Li
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Mengjiao Zhang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Gaolong Lin
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Sunkuan Hu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, China
| | - Helin Xu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China.
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3
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Ganji N, Li B, Lee C, Pierro A. Necrotizing enterocolitis: recent advances in treatment with translational potential. Pediatr Surg Int 2023; 39:205. [PMID: 37247104 DOI: 10.1007/s00383-023-05476-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/19/2023] [Indexed: 05/30/2023]
Abstract
Necrotizing enterocolitis (NEC) is one of the most prevalent and devastating gastrointestinal disorders in neonates. Despite advances in neonatal care, the incidence and mortality due to NEC remain high, highlighting the need to devise novel treatments for this disease. There have been a number of recent advancements in therapeutic approaches for the treatment of NEC; these involve remote ischemic conditioning (RIC), stem cell therapy, breast milk components (human milk oligosaccharides, exosomes, lactoferrin), fecal microbiota transplantation, and immunotherapy. This review summarizes the most recent advances in NEC treatment currently underway as well as their applicability and associated challenges and limitations, with the aim to provide new insight into the paradigm of care for NEC worldwide.
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Affiliation(s)
- Niloofar Ganji
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
- Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - Bo Li
- Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - Carol Lee
- Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada
| | - Agostino Pierro
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
- Translational Medicine, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada.
- Division of General and Thoracic Surgery, The Hospital for Sick Children, University of Toronto, 1526-555 University Ave, Toronto, ON, M5G 1X8, Canada.
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4
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Tung S, Delavogia E, Fernandez-Gonzalez A, Mitsialis SA, Kourembanas S. Harnessing the therapeutic potential of the stem cell secretome in neonatal diseases. Semin Perinatol 2023; 47:151730. [PMID: 36990921 PMCID: PMC10133192 DOI: 10.1016/j.semperi.2023.151730] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
Abstract
Preterm birth and intrapartum related complications account for a substantial amount of mortality and morbidity in the neonatal period despite significant advancements in neonatal-perinatal care. Currently, there is a noticeable lack of curative or preventative therapies available for any of the most common complications of prematurity including bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia and retinopathy of prematurity or hypoxic-ischemic encephalopathy, the main cause of perinatal brain injury in term infants. Mesenchymal stem/stromal cell-derived therapy has been an active area of investigation for the past decade and has demonstrated encouraging results in multiple experimental models of neonatal disease. It is now widely acknowledged that mesenchymal stem/stromal cells exert their therapeutic effects via their secretome, with the principal vector identified as extracellular vesicles. This review will focus on summarizing the current literature and investigations on mesenchymal stem/stromal cell-derived extracellular vesicles as a treatment for neonatal diseases and examine the considerations to their application in the clinical setting.
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Affiliation(s)
- Stephanie Tung
- Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA, United States; Department of Pediatrics, Harvard Medical School, Boston, MA, United States
| | - Eleni Delavogia
- Department of Pediatrics, Harvard Medical School, Boston, MA, United States; Department of Pediatrics, Massachusetts General Hospital for Children, Boston, MA, United States
| | - Angeles Fernandez-Gonzalez
- Division of Newborn Medicine, Department of Pediatrics, 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 Pediatrics, 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 Pediatrics, Boston Children's Hospital, Boston, MA, United States; Department of Pediatrics, Harvard Medical School, Boston, MA, United States.
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5
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Damianos A, Sammour I. Barriers in translating stem cell therapies for neonatal diseases. Semin Perinatol 2023; 47:151731. [PMID: 36990922 DOI: 10.1016/j.semperi.2023.151731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
Abstract
Over the last 20 years, stem cells of varying origin and their associated secretome have been investigated as a therapeutic option for a myriad of neonatal models of disease, with very promising results. Despite the devastating nature of some of these disorders, translation of the preclinical evidence to the bedside has been slow. In this review, we explore the existing clinical evidence for stem cell therapies in neonates, highlight the barriers faced by researchers and suggest potential solutions to move the field forward.
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Affiliation(s)
- Andreas Damianos
- Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, Ohio
| | - Ibrahim Sammour
- Riley Hospital for Children, Indiana University, Indianapolis, USA.
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6
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Di SJ, Wu SY, Liu TJ, Shi YY. Stem cell therapy as a promising strategy in necrotizing enterocolitis. Mol Med 2022; 28:107. [PMID: 36068527 PMCID: PMC9450300 DOI: 10.1186/s10020-022-00536-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/29/2022] [Indexed: 11/10/2022] Open
Abstract
Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease that affects newborns, particularly preterm infants, and is associated with high morbidity and mortality. No effective therapeutic strategies to decrease the incidence and severity of NEC have been developed to date. Stem cell therapy has been explored and even applied in various diseases, including gastrointestinal disorders. Animal studies on stem cell therapy have made great progress, and the anti-inflammatory, anti-apoptotic, and intestinal barrier enhancing effects of stem cells may be protective against NEC clinically. In this review, we discuss the therapeutic mechanisms through which stem cells may function in the treatment of NEC.
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Affiliation(s)
- Si-Jia Di
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Si-Yuan Wu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Tian-Jing Liu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Yong-Yan Shi
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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7
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Sodhi CP, Ahmad R, Jia H, Fulton WB, Lopez C, Gonzalez Salazar AJ, Ishiyama A, Sampah M, Steinway S, Wang S, Prindle T, Wang M, Steed DL, Wessel H, Kirshner Z, Brown LR, Lu P, Hackam DJ. The administration of amnion-derived multipotent cell secretome ST266 protects against necrotizing enterocolitis in mice and piglets. Am J Physiol Gastrointest Liver Physiol 2022; 323:G265-G282. [PMID: 35819175 PMCID: PMC9448291 DOI: 10.1152/ajpgi.00364.2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 06/27/2022] [Accepted: 06/29/2022] [Indexed: 01/31/2023]
Abstract
Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants and is steadily rising in frequency. Patients who develop NEC have a very high mortality, illustrating the importance of developing novel prevention or treatment approaches. We and others have shown that NEC arises in part from exaggerated signaling via the bacterial receptor, Toll-like receptor 4 (TLR4) on the intestinal epithelium, leading to widespread intestinal inflammation and intestinal ischemia. Strategies that limit the extent of TLR4 signaling, including the administration of amniotic fluid, can reduce NEC development in mouse and piglet models. We now seek to test the hypothesis that a secretome derived from amnion-derived cells can prevent or treat NEC in preclinical models of this disease via a process involving TLR4 inhibition. In support of this hypothesis, we show that the administration of this secretome, named ST266, to mice or piglets can prevent and treat experimental NEC. The protective effects of ST266 occurred in the presence of marked TLR4 inhibition in the intestinal epithelium of cultured epithelial cells, intestinal organoids, and human intestinal samples ex vivo, independent of epidermal growth factor. Strikingly, RNA-seq analysis of the intestinal epithelium in mice reveals that the ST266 upregulates critical genes associated with gut remodeling, intestinal immunity, gut differentiation. and energy metabolism. These findings show that the amnion-derived secretome ST266 can prevent and treat NEC, suggesting the possibility of novel therapeutic approaches for patients with this devastating disease.NEW & NOTEWORTHY This work provides hope for children who develop NEC, a devastating disease of premature infants that is often fatal, by revealing that the secreted product of amniotic progenitor cells (called ST266) can prevent or treat NEC in mice, piglet, and "NEC-in-a-dish" models of this disease. Mechanistically, ST266 prevented bacterial signaling, and a detailed transcriptomic analysis revealed effects on gut differentiation, immunity, and metabolism. Thus, an amniotic secretome may offer novel approaches for NEC.
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Affiliation(s)
- Chhinder P Sodhi
- Division of General Pediatric Surgery Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
- Department of Surgery, Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
| | - Raheel Ahmad
- Division of General Pediatric Surgery Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
- Department of Surgery, Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
| | - Hongpeng Jia
- Division of General Pediatric Surgery Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
- Department of Surgery, Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
| | - William B Fulton
- Division of General Pediatric Surgery Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
- Department of Surgery, Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
| | - Carla Lopez
- Division of General Pediatric Surgery Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
- Department of Surgery, Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
| | - Andres J Gonzalez Salazar
- Division of General Pediatric Surgery Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
- Department of Surgery, Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
| | - Asuka Ishiyama
- Division of General Pediatric Surgery Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
- Department of Surgery, Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
| | - Maame Sampah
- Division of General Pediatric Surgery Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
- Department of Surgery, Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
| | - Steve Steinway
- Division of General Pediatric Surgery Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
- Department of Surgery, Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
| | - Sanxia Wang
- Division of General Pediatric Surgery Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
- Department of Surgery, Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
| | - Thomas Prindle
- Division of General Pediatric Surgery Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
- Department of Surgery, Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
| | - Menghan Wang
- Division of General Pediatric Surgery Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
- Department of Surgery, Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
| | - David L Steed
- Noveome Biotherapeutics, Inc., Pittsburgh, Pennsylvania
| | - Howard Wessel
- Noveome Biotherapeutics, Inc., Pittsburgh, Pennsylvania
| | - Ziv Kirshner
- Noveome Biotherapeutics, Inc., Pittsburgh, Pennsylvania
| | - Larry R Brown
- Noveome Biotherapeutics, Inc., Pittsburgh, Pennsylvania
| | - Peng Lu
- Division of General Pediatric Surgery Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
- Department of Surgery, Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
| | - David J Hackam
- Division of General Pediatric Surgery Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
- Department of Surgery, Johns Hopkins University and Johns Hopkins Children's Center, Baltimore, Maryland
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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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9
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Amniotic fluid stem cell administration can prevent epithelial injury from necrotizing enterocolitis. Pediatr Res 2022; 91:101-106. [PMID: 34561550 DOI: 10.1038/s41390-021-01657-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 05/11/2021] [Accepted: 06/21/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Stem cell therapy has been proven to rescue intestinal injury and stimulate intestinal regeneration in necrotizing enterocolitis (NEC). Specifically, stem cells derived from amniotic fluid (AFSCs) and mesenchymal stem cells (MSCs) derived from bone marrow have shown promising results in the treatment of experimental NEC. This study aims to examine the effects of AFSCs and MSCs on the prevention of intestinal injury during experimental NEC. METHODS Supernatants from AFSC and MSC cultures were collected to perform proteomic analysis. Prior to NEC induction, mice received intraperitoneal injections of phosphate-buffered saline (PBS), 2 × 106 AFSCs, or 2 × 106 MSCs. RESULTS We found that AFSCs grew faster than MSCs. Proteomic analysis indicated that AFSCs are primarily involved in cell development and growth, while MSCs are involved in immune regulation. Administering AFSCs before NEC induction decreased NEC severity and mucosal inflammation. Intestinal proliferation and endogenous stem cell activation were increased after AFSC administration. However, administering MSCs before NEC induction had no beneficial effects. CONCLUSIONS This study demonstrated that AFSCs and MSCs have different protein release profiles. AFSCs can potentially be used as a preventative strategy for neonates at risk of NEC, while MSCs cannot be used. IMPACT AFSCs and MSCs have distinct protein secretory profiles, and AFSCs are primarily involved in cell development and growth, while MSCs are involved in immune regulation. AFSCs are unique in transiently enhancing healthy intestinal epithelial cell growth, which offers protection against the development of experimental NEC. The prevention of NEC via the administration of AFSCs should be evaluated in infants at great risk of developing NEC or in infants with early signs of NEC.
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Jones BC, Shibuya S, Durkin N, De Coppi P. Regenerative medicine for childhood gastrointestinal diseases. Best Pract Res Clin Gastroenterol 2021; 56-57:101769. [PMID: 35331401 DOI: 10.1016/j.bpg.2021.101769] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/30/2021] [Accepted: 10/08/2021] [Indexed: 01/31/2023]
Abstract
Several paediatric gastrointestinal diseases result in life-shortening organ failure. For many of these conditions, current therapeutic options are suboptimal and may not offer a cure. Regenerative medicine is an inter-disciplinary field involving biologists, engineers, and clinicians that aims to produce cell and tissue-based therapies to overcome organ failure. Exciting advances in stem cell biology, materials science, and bioengineering bring engineered gastrointestinal cell and tissue therapies to the verge of clinical trial. In this review, we summarise the requirements for bioengineered therapies, the possible sources of the various cellular and non-cellular components, and the progress towards clinical translation of oesophageal and intestinal tissue engineering to date.
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Affiliation(s)
- Brendan C Jones
- Stem Cell and Regenerative Medicine Section, Developmental Biology and Cancer Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; Specialist Neonatal and Paediatric Surgery Unit, Great Ormond Street Hospital, London, United Kingdom
| | - Soichi Shibuya
- Stem Cell and Regenerative Medicine Section, Developmental Biology and Cancer Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Natalie Durkin
- Stem Cell and Regenerative Medicine Section, Developmental Biology and Cancer Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; Specialist Neonatal and Paediatric Surgery Unit, Great Ormond Street Hospital, London, United Kingdom
| | - Paolo De Coppi
- Stem Cell and Regenerative Medicine Section, Developmental Biology and Cancer Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; Specialist Neonatal and Paediatric Surgery Unit, Great Ormond Street Hospital, London, United Kingdom.
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11
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Zeng R, Wang J, Zhuo Z, Luo Y, Sha W, Chen H. Stem cells and exosomes: promising candidates for necrotizing enterocolitis therapy. Stem Cell Res Ther 2021; 12:323. [PMID: 34090496 PMCID: PMC8180168 DOI: 10.1186/s13287-021-02389-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 05/13/2021] [Indexed: 02/08/2023] Open
Abstract
Necrotizing enterocolitis (NEC) is a devastating disease predominately affecting neonates. Despite therapeutic advances, NEC remains the leading cause of mortality due to gastrointestinal conditions in neonates. Stem cells have been exploited in various diseases, and the application of different types of stem cells in the NEC therapy is explored in the past decade. However, stem cell transplantation possesses several deficiencies, and exosomes are considered potent alternatives. Exosomes, especially those derived from stem cells and breast milk, demonstrate beneficial effects for NEC both in vivo and in vitro and emerge as promising options for clinical practice. In this review, the function and therapeutic effects of stem cells and exosomes for NEC are investigated and summarized, which provide insights for the development and application of novel therapeutic strategies in pediatric diseases. Further elucidation of mechanisms, improvement in preparation, bioengineering, and administration, as well as rigorous clinical trials are warranted.
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Affiliation(s)
- Ruijie Zeng
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Shantou University Medical College, Shantou, 515041, China
| | - Jinghua Wang
- Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Zewei Zhuo
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Yujun Luo
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Weihong Sha
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
| | - Hao Chen
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
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12
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Weis VG, Deal AC, Mekkey G, Clouse C, Gaffley M, Whitaker E, Peeler CB, Weis JA, Schwartz MZ, Atala A. Human placental-derived stem cell therapy ameliorates experimental necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 2021; 320:G658-G674. [PMID: 33566727 PMCID: PMC8238163 DOI: 10.1152/ajpgi.00369.2020] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 02/08/2021] [Accepted: 02/08/2021] [Indexed: 02/06/2023]
Abstract
Necrotizing enterocolitis (NEC), a life-threatening intestinal disease, is becoming a larger proportionate cause of morbidity and mortality in premature infants. To date, therapeutic options remain elusive. Based on recent cell therapy studies, we investigated the effect of a human placental-derived stem cell (hPSC) therapy on intestinal damage in an experimental NEC rat pup model. NEC was induced in newborn Sprague-Dawley rat pups for 4 days via formula feeding, hypoxia, and LPS. NEC pups received intraperitoneal (ip) injections of either saline or hPSC (NEC-hPSC) at 32 and 56 h into NEC induction. At 4 days, intestinal macroscopic and histological damage, epithelial cell composition, and inflammatory marker expression of the ileum were assessed. Breastfed (BF) littermates were used as controls. NEC pups developed significant bowel dilation and fragility in the ileum. Further, NEC induced loss of normal villi-crypt morphology, disruption of epithelial proliferation and apoptosis, and loss of critical progenitor/stem cell and Paneth cell populations in the crypt. hPSC treatment improved macroscopic intestinal health with reduced ileal dilation and fragility. Histologically, hPSC administration had a significant reparative effect on the villi-crypt morphology and epithelium. In addition to a trend of decreased inflammatory marker expression, hPSC-NEC pups had increased epithelial proliferation and decreased apoptosis when compared with NEC littermates. Further, the intestinal stem cell and crypt niche that include Paneth cells, SOX9+ cells, and LGR5+ stem cells were restored with hPSC therapy. Together, these data demonstrate hPSC can promote epithelial healing of NEC intestinal damage.NEW & NOTEWORTHY These studies demonstrate a human placental-derived stem cell (hPSC) therapeutic strategy for necrotizing enterocolitis (NEC). In an experimental model of NEC, hPSC administration improved macroscopic intestinal health, ameliorated epithelial morphology, and supported the intestinal stem cell niche. Our data suggest that hPSC are a potential therapeutic approach to attenuate established intestinal NEC damage. Further, we show hPSC are a novel research tool that can be utilized to elucidate critical neonatal repair mechanisms to overcome NEC.
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Affiliation(s)
- Victoria G Weis
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina
| | - Anna C Deal
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina
| | - Gehad Mekkey
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina
- Faculty of Science, Zagazig University, Zagazig, Egypt
| | - Cara Clouse
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina
| | - Michaela Gaffley
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina
- General Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Emily Whitaker
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina
| | - Cole B Peeler
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina
- School of Biomedical Engineering and Sciences, Virginia Tech-Wake Forest University, Blacksburg, Virginia
| | - Jared A Weis
- School of Biomedical Engineering and Sciences, Virginia Tech-Wake Forest University, Blacksburg, Virginia
- Department of Biomedical Engineering, Wake Forest School of Medicine, Winston-Salem, North Carolina
- Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina
| | - Marshall Z Schwartz
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina
| | - Anthony Atala
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina
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Villamor-Martinez E, Hundscheid T, Kramer BW, Hooijmans CR, Villamor E. Stem Cells as Therapy for Necrotizing Enterocolitis: A Systematic Review and Meta-Analysis of Preclinical Studies. Front Pediatr 2020; 8:578984. [PMID: 33363060 PMCID: PMC7755993 DOI: 10.3389/fped.2020.578984] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 10/13/2020] [Indexed: 12/23/2022] Open
Abstract
Background: Necrotizing enterocolitis (NEC) is the most common life-threatening gastrointestinal condition among very and extremely preterm infants. Stem cell therapy has shown some promising protective effects in animal models of intestinal injury, including NEC, but no systematic review has yet evaluated the preclinical evidence of stem cell therapy for NEC prevention or treatment. Methods: PubMed and EMBASE databases were searched for studies using an animal model of NEC with stem cells or their products. The SYRCLE tool was used for the assessment of risk of bias. A random-effects model was used to pool odds ratios (ORs) and 95% confidence interval (CI). Results: We screened 953 studies, of which nine (eight rat and one mouse models) met the inclusion criteria. All animal models induced NEC by a combination of hypothermia, hypoxia, and formula feeding. Risk of bias was evaluated as unclear on most items for all studies included. Meta-analysis found that both mesenchymal and neural stem cells and stem cell-derived exosomes reduced the incidence of all NEC (OR 0.22, 95% CI 0.16-0.32, k = 16), grade 2 NEC (OR 0.41, 95% CI 0.24-0.70, k = 16), and grade 3-4 NEC (OR 0.28, 95% CI 0.19-0.42, k = 16). k represents the number of independent effect sizes included in each meta-analysis. The effect of the exosomes was similar to that of the stem cells. Stem cells and exosomes also improved 4-day survival (OR 2.89 95% CI 2.07-4.04, k = 9) and 7-day survival (OR 3.96 95% CI 2.39-6.55, k = 5) after experimental NEC. Meta-analysis also found that stem cells reduced other indicators of intestinal injury. Conclusion: The data from this meta-analysis suggest that both stem cells and stem cell-derived exosomes prevented NEC in rodent experimental models. However, unclear risk of bias and incomplete reporting underline that poor reporting standards are common and hamper the reliable interpretation of preclinical evidence for stem cell therapy for NEC.
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Affiliation(s)
- Eduardo Villamor-Martinez
- Department of Pediatrics, Maastricht University Medical Center (MUMC+), School for Oncology and Developmental Biology (GROW), Maastricht, Netherlands
| | - Tamara Hundscheid
- Department of Pediatrics, Maastricht University Medical Center (MUMC+), School for Oncology and Developmental Biology (GROW), Maastricht, Netherlands
| | - Boris W. Kramer
- Department of Pediatrics, Maastricht University Medical Center (MUMC+), School for Oncology and Developmental Biology (GROW), Maastricht, Netherlands
| | - Carlijn R Hooijmans
- Department for Health Evidence Unit SYRCLE, Radboud University Medical Center, Nijmegen, Netherlands
| | - Eduardo Villamor
- Department of Pediatrics, Maastricht University Medical Center (MUMC+), School for Oncology and Developmental Biology (GROW), Maastricht, Netherlands
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14
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Amniotic fluid and breast milk: a rationale for breast milk stem cell therapy in neonatal diseases. Pediatr Surg Int 2020; 36:999-1007. [PMID: 32671487 DOI: 10.1007/s00383-020-04710-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/30/2020] [Indexed: 12/18/2022]
Abstract
Amniotic fluid and breast milk play important roles in structural development throughout fetal growth and infancy. Given their significance in physical maturation, many studies have investigated the therapeutic and protective roles of amniotic fluid and breast milk in neonatal diseases. Of particular interest to researchers are stem cells found in the two fluids. These stem cells have been investigated due to their ability to self-replicate, differentiate, reduce tissue damage, and their expression of pluripotent markers. While amniotic fluid stem cells have received some attention regarding their ability to treat neonatal diseases, breast milk stem cells have not been investigated to the same extent given the recency of their discovery. The purpose of this review is to compare the functions of amniotic fluid, breast milk, and their stem cells to provide a rationale for the use of breast milk stem cells as a therapy for neonatal diseases. Breast milk stem cells present as an important tool for treating neonatal diseases given their ability to reduce inflammation and tissue damage, as well as their multilineage differentiation potential, easy accessibility, and ability to be used in disease modelling.
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15
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Pammi M, De Plaen IG, Maheshwari A. Recent Advances in Necrotizing Enterocolitis Research: Strategies for Implementation in Clinical Practice. Clin Perinatol 2020; 47:383-397. [PMID: 32439118 PMCID: PMC7245582 DOI: 10.1016/j.clp.2020.02.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Necrotizing enterocolitis (NEC) is a complex inflammatory necrosis of the neonatal intestine, which is likely to require a multipronged approach for prevention and treatment. Despite identifying and defining NEC as a disease entity several decades back, no major progress has been made toward its early identification, treatment, or prevention. This article reviews the latest research strategies that are currently ongoing for early diagnosis and monitoring and prevention of the disease.
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Affiliation(s)
- Mohan Pammi
- Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA
| | - Isabelle G. De Plaen
- Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
| | - Akhil Maheshwari
- Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD, USA.
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16
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Therapeutic Effects of Mesenchymal Stem Cells Derived From Bone Marrow, Umbilical Cord Blood, and Pluripotent Stem Cells in a Mouse Model of Chemically Induced Inflammatory Bowel Disease. Inflammation 2020; 42:1730-1740. [PMID: 31227956 DOI: 10.1007/s10753-019-01033-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Acute inflammatory bowel disease (AIBD) is a wide clinical entity including severe gastrointestinal pathologies with common histopathological basis. Epidemiologically increasing diseases, such as necrotizing enterocolitis (NEC), gastrointestinal graft versus host disease (GVHD), and the primary acute phase of chronic inflammatory bowel disease (CIBD), exhibit a high necessity for new therapeutic strategies. Mesenchymal stem cell (MSC) cellular therapy represents a promising option for the treatment of these diseases. In our study, we comparatively assess the efficacy of human MSCs derived from bone marrow (BM), umbilical cord blood (UCB), human embryonic stem cells (ESCs), or human-induced pluripotent stem cells (iPSCs) in a mouse model of chemically induced acute enterocolitis. The laboratory animals were provided ad libitum potable dextrane sulfate sodium solution (DSS) in order to reproduce an AIBD model and then individually exposed intraperitoneally to MSCs derived from BM (BM-MSCs), UCB (UCB-MSCs), ESCs (ESC-MSCs), or iPSCs (iPSC-MSCs). The parameters used to evaluate the cellular treatment efficacy were the animal survival prolongation and the histopathological-macroscopic picture of bowel sections. Although all categories of mesenchymal stem cells led to statistically significant survival prolongation compared to the control group, significant clinical and histopathological improvement was observed only in mice receiving BM-MSCs and UCB-MSCs. Our results demonstrated that the in vivo anti-inflammatory effect of ESC-MSCs and iPSC-MSCs was inferior to that of UCB-MSCs and BM-MSCs. Further investigation will clarify the potential of ESCs and iPSC-derived MSCs in AIBD treatment.
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17
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Nitkin CR, Rajasingh J, Pisano C, Besner GE, Thébaud B, Sampath V. Stem cell therapy for preventing neonatal diseases in the 21st century: Current understanding and challenges. Pediatr Res 2020; 87:265-276. [PMID: 31086355 PMCID: PMC6854309 DOI: 10.1038/s41390-019-0425-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 04/24/2019] [Indexed: 02/06/2023]
Abstract
Diseases of the preterm newborn such as bronchopulmonary dysplasia, necrotizing enterocolitis, cerebral palsy, and hypoxic-ischemic encephalopathy continue to be major causes of infant mortality and long-term morbidity. Effective therapies for the prevention or treatment for these conditions are still lacking as recent clinical trials have shown modest or no benefit. Stem cell therapy is rapidly emerging as a novel therapeutic tool for several neonatal diseases with encouraging pre-clinical results that hold promise for clinical translation. However, there are a number of unanswered questions and facets to the development of stem cell therapy as a clinical intervention. There is much work to be done to fully elucidate the mechanisms by which stem cell therapy is effective (e.g., anti-inflammatory versus pro-angiogenic), identifying important paracrine mediators, and determining the timing and type of therapy (e.g., cellular versus secretomes), as well as patient characteristics that are ideal. Importantly, the interaction between stem cell therapy and current, standard-of-care interventions is nearly completely unknown. In this review, we will focus predominantly on the use of mesenchymal stromal cells for neonatal diseases, highlighting the promises and challenges in clinical translation towards preventing neonatal diseases in the 21st century.
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Affiliation(s)
- Christopher R Nitkin
- Division of Neonatology, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, MO, USA
| | - Johnson Rajasingh
- Department of Cardiovascular Medicine, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, MO, USA
| | - Courtney Pisano
- Department of Pediatric Surgery, Center for Perinatal Research, Nationwide Children's Hospital, Columbus, OH, USA
| | - Gail E Besner
- Department of Pediatric Surgery, Center for Perinatal Research, Nationwide Children's Hospital, Columbus, OH, USA
| | - Bernard Thébaud
- Division of Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario (CHEO) and CHEO Research Institute, Ottawa, ON, Canada
- Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada
| | - Venkatesh Sampath
- Division of Neonatology, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, MO, USA.
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18
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Drucker NA, Te Winkel JP, Shelley WC, Olson KR, Markel TA. Inhibiting hydrogen sulfide production in umbilical stem cells reduces their protective effects during experimental necrotizing enterocolitis. J Pediatr Surg 2019; 54:1168-1173. [PMID: 30879750 PMCID: PMC6545254 DOI: 10.1016/j.jpedsurg.2019.02.037] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Accepted: 02/21/2019] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Umbilical mesenchymal stem cells (USC) have been shown to reduce illness in animal models of necrotizing enterocolitis (NEC), possibly through the paracrine release of hydrogen sulfide (H2S). We hypothesized that animals treated with USCs with inhibited H2S synthesis would exhibit more severe disease. METHODS NEC was induced in five-day-old mouse pups by formula feeding and hypoxic and hypothermic stress. Experimental groups received intraperitoneal injection of either saline vehicle or 80,000cells/gram of one of the following cell types: USC, USCs with negative-control siRNA, or USCs with targeted siRNA inhibition of the H2S-producing enzymes. Pups were monitored by clinical assessment and after euthanasia, intestine and lung histologic injury were scored. Tissue was homogenized, and concentrations of IL-6, IL-10, and VEGF were determined by ELISA. For statistical analysis, p<0.05 was considered significant. RESULTS Animals treated with negative-control siRNA USCs were significantly improved compared to vehicle. Clinical sickness scores as well as intestinal and lung histologic injury scores in the targeted siRNA groups were significantly worse when compared to the negative-control siRNA group. IL-6, IL-10, and VEGF had varying patterns of expression in the different groups. CONCLUSION Inhibition of H2S production in USCs reduces the beneficial effects of these cells during therapy in experimental NEC. LEVEL OF EVIDENCE Animal studies are typically described as "foundational evidence" without a true level assigned. TYPE OF STUDY Animal Study.
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Affiliation(s)
- Natalie A Drucker
- Department of Surgery, Section of Pediatric Surgery, Riley Hospital for Children at Indiana University Health, Indianapolis, IN; The Indiana University School of Medicine, Indianapolis, Indianapolis, IN.
| | - Jan P Te Winkel
- Department of Surgery, Section of Pediatric Surgery, Riley Hospital for Children at Indiana University Health, Indianapolis, IN; The Indiana University School of Medicine, Indianapolis, Indianapolis, IN
| | - W Christopher Shelley
- Department of Surgery, Section of Pediatric Surgery, Riley Hospital for Children at Indiana University Health, Indianapolis, IN
| | - Kenneth R Olson
- The Indiana University School of Medicine, South Bend, South Bend, IN
| | - Troy A Markel
- Department of Surgery, Section of Pediatric Surgery, Riley Hospital for Children at Indiana University Health, Indianapolis, IN; The Indiana University School of Medicine, Indianapolis, Indianapolis, IN
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19
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Loukogeorgakis SP, De Coppi P. Concise Review: Amniotic Fluid Stem Cells: The Known, the Unknown, and Potential Regenerative Medicine Applications. Stem Cells 2018; 35:1663-1673. [PMID: 28009066 DOI: 10.1002/stem.2553] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 09/07/2016] [Accepted: 10/01/2016] [Indexed: 12/19/2022]
Abstract
The amniotic fluid has been identified as an untapped source of cells with broad potential, which possess immunomodulatory properties and do not have the ethical and legal limitations of embryonic stem cells. CD117(c-Kit)+ cells selected from amniotic fluid have been shown to differentiate into cell lineages representing all three embryonic germ layers without generating tumors, making them ideal candidates for regenerative medicine applications. Moreover, their ability to engraft in injured organs and modulate immune and repair responses of host tissues, suggest that transplantation of such cells may be useful for the treatment of various degenerative and inflammatory diseases. Although significant questions remain regarding the origin, heterogeneous phenotype, and expansion potential of amniotic fluid stem cells, evidence to date supports their potential role as a valuable stem cell source for the field of regenerative medicine. Stem Cells 2017;35:1663-1673.
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Affiliation(s)
- Stavros P Loukogeorgakis
- Stem Cells and Regenerative Medicine Section, Developmental Biology and Cancer Programme, Institute of Child Health, University College London, London, United Kingdom
| | - Paolo De Coppi
- Stem Cells and Regenerative Medicine Section, Developmental Biology and Cancer Programme, Institute of Child Health, University College London, London, United Kingdom
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20
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Abstract
Necrotizing enterocolitis (NEC) continues to afflict approximately 7% of preterm infants born weighing less than 1500g, though recent investigations have provided novel insights into the pathogenesis of this complex disease. The disease has been a major cause of morbidity and mortality in neonatal intensive care units worldwide for many years, and our current understanding reflects exceptional observations made decades ago. In this review, we will describe NEC from a historical context and summarize seminal findings that underscore the importance of enteral feeding, the gut microbiota, and intestinal inflammation in this complex pathophysiology.
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Affiliation(s)
- David Hackam
- Division of Pediatric General Surgery, Department of Surgery, Johns Hopkins Children's Center and The Johns Hopkins University, Baltimore, MD.
| | - Michael Caplan
- North Shore University Health System and the University of Chicago Pritzker School of Medicine
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21
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McCulloh CJ, Olson JK, Zhou Y, Wang Y, Besner GE. Stem cells and necrotizing enterocolitis: A direct comparison of the efficacy of multiple types of stem cells. J Pediatr Surg 2017; 52:999-1005. [PMID: 28366560 PMCID: PMC5467690 DOI: 10.1016/j.jpedsurg.2017.03.028] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Accepted: 03/09/2017] [Indexed: 02/06/2023]
Abstract
PURPOSE Necrotizing enterocolitis (NEC) is a leading cause of gastrointestinal morbidity and mortality in premature infants. While studies have shown potential for stem cell (SC) therapy in experimental NEC, no study has compared different SC side-by-side. Our purpose was to determine whether one type of SC may more effectively treat NEC than others. METHODS Four SC were compared: (1) amniotic fluid-derived mesenchymal SC (AF-MSC); (2) amniotic fluid-derived neural SC (AF-NSC); (3) bone marrow-derived mesenchymal SC (BM-MSC); and (4) neonatal enteric neural SC (E-NSC). Using an established rat model of NEC, pups delivered prematurely received an intraperitoneal injection of SC. Control pups were injected with PBS. Additional controls were breast-fed by surrogates and not subjected to experimental NEC. Intestinal tissue was graded histologically. RESULTS NEC incidence was: PBS, 61.3%; breast-fed unstressed, 0%; AF-MSC, 19.1%; BM-MSC, 22.9%; AF-NSC, 18.9%; E-NSC 22.2%. All groups demonstrated statistical significance (p<0.05) compared to controls, and there was no difference between SC groups. CONCLUSION All four SC groups reduced the incidence and severity of experimental NEC equivalently. AF-MSC may be preferable because of availability of AF at delivery and ease of expansion, increasing potential for clinical translation. LEVEL OF EVIDENCE V (Animal study).
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22
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Evaluating the efficacy of different types of stem cells in preserving gut barrier function in necrotizing enterocolitis. J Surg Res 2017. [PMID: 28624056 DOI: 10.1016/j.jss.2017.03.026] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. Increased intestinal permeability is central to NEC development. We have shown that stem cells (SCs) can reduce the incidence and severity of NEC. Our current goal was to investigate the efficacy of four different types of SC in preservation of gut barrier function during NEC. MATERIALS AND METHODS We compared (1) amniotic fluid-derived mesenchymal SC, (2) bone marrow-derived mesenchymal SC, (3) amniotic fluid-derived neural SC, and (4) enteric neural SC. Premature rat pups received an intraperitoneal injection of 2 × 106 SC or phosphate-buffered saline only and were then subjected to experimental NEC. Control pups were breastfed and not subjected to NEC. After 48 h, animals received a single enteral dose of fluorescein isothiocyanate -labeled dextran (FD70), were sacrificed 4 h later, and serum FD70 concentrations determined. RESULTS Compared to breastfed, unstressed pups with intact gut barrier function and normal intestinal permeability (serum FD70 concentration 2.22 ± 0.271 μg/mL), untreated pups exposed to NEC had impaired barrier function with significantly increased permeability (18.6 ± 4.25 μg/mL, P = 0.047). Pups exposed to NEC but treated with SC had significantly reduced intestinal permeability: Amniotic fluid-derived mesenchymal SC (9.45 ± 1.36 μg/mL, P = 0.017), bone marrow-derived mesenchymal SC (6.73 ± 2.74 μg/mL, P = 0.049), amniotic fluid-derived neural SC (8.052 ± 1.31 μg/mL, P = 0.0496), and enteric neural SC (6.60 ± 1.46 μg/mL, P = 0.033). CONCLUSIONS SCs improve gut barrier function in experimental NEC. Although all four types of SC reduce permeability equivalently, SC derived from amniotic fluid may be preferable due to availability at delivery and ease of culture, potentially enhancing clinical translation.
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23
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Bohlin K. Cell-based strategies to reconstitute vital functions in preterm infants with organ failure. Best Pract Res Clin Obstet Gynaecol 2016; 31:99-111. [DOI: 10.1016/j.bpobgyn.2015.08.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 08/31/2015] [Indexed: 12/14/2022]
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Abstract
Necrotizing enterocolitis is a devastating intestinal disease that affects ~5% of preterm neonates. Despite advancements in neonatal care, mortality remains high (30–50%) and controversy still persists with regards to the most appropriate management of neonates with necrotizing enterocolitis. Herein, we review some controversial aspects regarding the epidemiology, imaging, medical and surgical management of necrotizing enterocolitis and we describe new emerging strategies for prevention and treatment.
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Affiliation(s)
- Augusto Zani
- Division of General and Thoracic Surgery, University of Toronto, The Hospital for Sick Children, Toronto, Canada
| | - Agostino Pierro
- Division of General and Thoracic Surgery, University of Toronto, The Hospital for Sick Children, Toronto, Canada
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Flores AI, Gómez-Gómez GJ, Masedo-González &A, Martínez-Montiel MP. Stem cell therapy in inflammatory bowel disease: A promising therapeutic strategy? World J Stem Cells 2015; 7:343-351. [PMID: 25815119 PMCID: PMC4369491 DOI: 10.4252/wjsc.v7.i2.343] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 09/24/2014] [Accepted: 11/10/2014] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases are inflammatory, chronic and progressive diseases of the intestinal tract for which no curative treatment is available. Research in other fields with stem cells of different sources and with immunoregulatory cells (regulatory T-lymphocytes and dendritic T-cells) opens up new expectations for their use in these diseases. The goal for stem cell-based therapy is to provide a permanent cure. To achieve this, it will be necessary to obtain a cellular product, original or genetically modified, that has a high migration capacity and homes into the intestine, has high survival after transplantation, regulates the immune reaction while not being visible to the patient’s immune system, and repairs the injured tissue.
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