2 PLACENTAL-DERIVED STEM CELLS AMELIORATE INTESTINAL DAMAGE AND CELL DYSREGULATION IN EXPERIMENTAL NECROTIZING ENTEROCOLITIS

2020 ◽  
Vol 158 (6) ◽  
pp. S-1
Author(s):  
Victoria G. Weis ◽  
Anna C. Deal ◽  
Gehad Mekky ◽  
Cara Clouse ◽  
Michaela Gaffley ◽  
...  
Keyword(s):  
Stem Cells ◽  
Necrotizing Enterocolitis ◽  
Intestinal Damage

scholarly journals Human placental-derived stem cell therapy ameliorates experimental necrotizing enterocolitis and supports restoration of the intestinal stem cell niche

2020 ◽  
Author(s):  
Victoria G. Weis ◽  
Anna C. Deal ◽  
Gehad Mekkey ◽  
Cara Clouse ◽  
Michaela Gaffley ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Therapy ◽  
Necrotizing Enterocolitis ◽  
Stem Cell Niche ◽  
Inflammatory Marker ◽  
Intestinal Stem Cell ◽  
Intestinal Damage ◽  
Epithelial Proliferation ◽  
Cell Niche

AbstractNecrotizing 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 hours into NEC induction. At 4 days, intestinal macroscopic and histological damage, epithelial cell composition, and inflammatory marker expression of the ileum was 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 Paneth cells and LGR5+ stem cells 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 to NEC littermates. Further, the intestinal stem cell niche of Paneth cells and LGR5+ stem cells was increased with hPSC therapy. Together, these data demonstrate hPSC can promote epithelial healing of NEC intestinal damage in part through support of the intestinal stem cell niche.New and NoteworthyThese 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 now be utilized to elucidate critical neonatal repair mechanisms to overcome NEC disease.

scholarly journals Treatment of necrotizing enterocolitis by conditioned medium derived from human amniotic fluid stem cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0260522
Author(s):  
Joshua S. O’Connell ◽  
Bo Li ◽  
Andrea Zito ◽  
Abdalla Ahmed ◽  
Marissa Cadete ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Amniotic Fluid ◽  
Conditioned Medium ◽  
Necrotizing Enterocolitis ◽  
Cell Activity ◽  
Intestinal Injury ◽  
Intestinal Damage ◽  
Amniotic Fluid Stem Cells ◽  
Stem Cell Activity

Purpose Necrotizing enterocolitis (NEC) is one of the most distressing gastrointestinal emergencies affecting neonates. Amniotic fluid stem cells (AFSC) improve intestinal injury and survival in experimental NEC but are difficult to administer. In this study, we evaluated whether conditioned medium (CM) derived from human AFSC have protective effects. Methods Three groups of C57BL/6 mice were studied: (i) breast-fed mice as control; (ii) experimental NEC mice receiving PBS; and (iii) experimental NEC mice receiving CM. NEC was induced between post-natal days P5 through P9 via: (A) gavage feeding of hyperosmolar formula four-time a day; (B) 10 minutes hypoxia prior to feeds; and (C) lipopolysaccharide administration on P6 and P7. Intra-peritoneal injections of either PBS or CM were given on P6 and P7. All mice were sacrificed on P9 and terminal ileum were harvested for analyses. Results CM treatment increased survival and reduced intestinal damage, decreased mucosal inflammation (IL-6; TNF-α), neutrophil infiltration (MPO), and apoptosis (CC3), and also restored angiogenesis (VEGF) in the ileum. Additionally, CM treated mice had increased levels of epithelial proliferation (Ki67) and stem cell activity (Olfm4; Lgr5) compared to NEC+PBS mice, showing restored intestinal regeneration and recovery during NEC induction. CM proteomic analysis of CM content identified peptides that regulated immune and stem cell activity. Conclusions CM derived from human AFSC administered in experimental NEC exhibited various benefits including reduced intestinal injury and inflammation, increased enterocyte proliferation, and restored intestinal stem cell activity. This study provides the scientific basis for the use of CM derived from AFSC in neonates with NEC.

scholarly journals Stem cells and exosomes: promising candidates for necrotizing enterocolitis therapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ruijie Zeng ◽  
Jinghua Wang ◽  
Zewei Zhuo ◽  
Yujun Luo ◽  
Weihong Sha ◽  
...  
Keyword(s):  
Stem Cells ◽  
Necrotizing Enterocolitis ◽  
Therapeutic Effects ◽  
Beneficial Effects ◽  
Pediatric Diseases ◽  
Gastrointestinal Conditions ◽  
Different Types ◽  
Novel Therapeutic Strategies

AbstractNecrotizing 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.

scholarly journals Use of organoids to study regenerative responses to intestinal damage

2019 ◽  
Vol 317 (6) ◽  
pp. G845-G852 ◽  
Author(s):  
Sarah E. Blutt ◽  
Ophir D. Klein ◽  
Mark Donowitz ◽  
Noah Shroyer ◽  
Chandan Guha ◽  
...  
Keyword(s):  
Stem Cells ◽  
Parasitic Infection ◽  
Genetically Modify ◽  
Intestinal Wall ◽  
Intestinal Damage ◽  
Therapeutic Modalities ◽  
Epithelial Regeneration ◽  
Vitro Model ◽  
Induced Pluripotent

Intestinal organoid cultures provide an in vitro model system for studying pathways and mechanisms involved in epithelial damage and repair. Derived from either embryonic or induced pluripotent stem cells or adult intestinal stem cells or tissues, these self-organizing, multicellular structures contain polarized mature cells that recapitulate both the physiology and heterogeneity of the intestinal epithelium. These cultures provide a cutting-edge technology for defining regenerative pathways that are induced following radiation or chemical damage, which directly target the cycling intestinal stem cell, or damage resulting from viral, bacterial, or parasitic infection of the epithelium. Novel signaling pathways or biological mechanisms identified from organoid studies that mediate regeneration of the epithelium following damage are likely to be important targets of preventive or therapeutic modalities to mitigate intestinal injury. The evolution of these cultures to include more components of the intestinal wall and the ability to genetically modify them are key components for defining the mechanisms that modulate epithelial regeneration.

scholarly journals Remote ischemic conditioning counteracts the intestinal damage of necrotizing enterocolitis by improving intestinal microcirculation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yuhki Koike ◽  
Bo Li ◽  
Niloofar Ganji ◽  
Haitao Zhu ◽  
Hiromu Miyake ◽  
...  
Keyword(s):  
Necrotizing Enterocolitis ◽  
Mechanism Of Action ◽  
Intestinal Inflammation ◽  
Intestinal Damage ◽  
Invasive Treatment ◽  
Remote Ischemic Conditioning ◽  
Ischemic Conditioning ◽  
Non Invasive ◽  
Intestinal Microcirculation ◽  
Promising Tool

Abstract Necrotizing enterocolitis (NEC) is a devastating disease of premature infants with high mortality rate, indicating the need for precision treatment. NEC is characterized by intestinal inflammation and ischemia, as well derangements in intestinal microcirculation. Remote ischemic conditioning (RIC) has emerged as a promising tool in protecting distant organs against ischemia-induced damage. However, the effectiveness of RIC against NEC is unknown. To address this gap, we aimed to determine the efficacy and mechanism of action of RIC in experimental NEC. NEC was induced in mouse pups between postnatal day (P) 5 and 9. RIC was applied through intermittent occlusion of hind limb blood flow. RIC, when administered in the early stages of disease progression, decreases intestinal injury and prolongs survival. The mechanism of action of RIC involves increasing intestinal perfusion through vasodilation mediated by nitric oxide and hydrogen sulfide. RIC is a viable and non-invasive treatment strategy for NEC.

scholarly journals Stem cells and necrotizing enterocolitis: A direct comparison of the efficacy of multiple types of stem cells

2017 ◽  
Vol 52 (6) ◽  
pp. 999-1005 ◽  
Author(s):  
Christopher J. McCulloh ◽  
Jacob K. Olson ◽  
Yu Zhou ◽  
Yijie Wang ◽  
Gail E. Besner
Keyword(s):  
Stem Cells ◽  
Necrotizing Enterocolitis

scholarly journals Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage

2015 ◽  
Vol 212 (11) ◽  
pp. 1783-1791 ◽  
Author(s):  
Patricia Aparicio-Domingo ◽  
Monica Romera-Hernandez ◽  
Julien J. Karrich ◽  
Ferry Cornelissen ◽  
Natalie Papazian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Tissue Damage ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Intestinal Damage ◽  
Intestinal Epithelial ◽  
Epithelial Stem Cells ◽  
Intestinal Tissue ◽  
Mucosal Surfaces ◽  
Type 3

Disruption of the intestinal epithelial barrier allows bacterial translocation and predisposes to destructive inflammation. To ensure proper barrier composition, crypt-residing stem cells continuously proliferate and replenish all intestinal epithelial cells within days. As a consequence of this high mitotic activity, mucosal surfaces are frequently targeted by anticancer therapies, leading to dose-limiting side effects. The cellular mechanisms that control tissue protection and mucosal healing in response to intestinal damage remain poorly understood. Type 3 innate lymphoid cells (ILC3s) are regulators of homeostasis and tissue responses to infection at mucosal surfaces. We now demonstrate that ILC3s are required for epithelial activation and proliferation in response to small intestinal tissue damage induced by the chemotherapeutic agent methotrexate. Multiple subsets of ILC3s are activated after intestinal tissue damage, and in the absence of ILC3s, epithelial activation is lost, correlating with increased pathology and severe damage to the intestinal crypts. Using ILC3-deficient Lgr5 reporter mice, we show that maintenance of intestinal stem cells after damage is severely impaired in the absence of ILC3s or the ILC3 signature cytokine IL-22. These data unveil a novel function of ILC3s in limiting tissue damage by preserving tissue-specific stem cells.

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