Human placental-derived stem cell therapy ameliorates experimental necrotizing enterocolitis

Weis, Victoria G.; Deal, Anna; Mekky, Gehad; Clouse, Cara; Gaffley, Michaela; Whitaker, Emily; Peeler, Cole B.; Weis, Jared A.; Schwartz, Marshall Z.; Atala, Anthony

doi:10.1152/ajpgi.00369.2020

Cited by 20 publications

(24 citation statements)

References 87 publications

(135 reference statements)

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“…There are several animal studies that showcase the benefits of MSCs to mitigate the intestinal pathogenesis of NEC. In rat models of NEC, intraperitoneal(IP) injections of MSCs have shown an improvement in clinical sickness and intestinal histology injury—characterized by restoration of villi-crypt morphology and epithelium along with restoration of populations of Paneth cells, SOX9 cells, and LGR5 stem cells that occupy this crypt niche ( 98 , 99 ). An adult mouse-model of ischemia and reperfusion utilized several different MSC's including umbilical cord (UC-MSC), bone-marrow (BM-MSC), and adipocyte-derived (AD-MSCs) cells and similarly showed improved overall survival, intestinal perfusion, restoration of normal intestinal histology, and a decrease in pro-inflammatory chemokines ( 84 , 100 ).…”

Section: Therapies In Perinatal Brain Injurymentioning

confidence: 99%

Gut-Brain cross talk: The pathogenesis of neurodevelopmental impairment in necrotizing enterocolitis

Manohar

Mesfin²,

Liu³

et al. 2023

Front. Pediatr.

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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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Section: Therapies In Perinatal Brain Injurymentioning

confidence: 99%

Gut-Brain cross talk: The pathogenesis of neurodevelopmental impairment in necrotizing enterocolitis

Manohar

Mesfin²,

Liu³

et al. 2023

Front. Pediatr.

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“…NEC is a life-threatening intestinal disease in premature infants (Weis et al, 2021), however, the pathophysiology of NEC remains incompletely understood (Frost et al, 2017). Although NEC’s pathogenesis is multifactorial, Paneth cell depletion or dysfunction has been linked mechanistically to development of NEC (Lueschow and McElroy, 2020).…”

Section: Discussionmentioning

confidence: 99%

LSR Targets YAP to Modulate Intestinal Paneth Cell Differentiation

Wang

Fan

et al. 2022

Preprint

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Lipolysis-stimulated lipoprotein receptor (LSR) is a multi‐functional protein that is best known for its roles in assembly of epithelial tricellular tight junctions and hepatic clearance of lipoproteins. Here, we investigate the function of LSR in intestine biology. By using multiple conditional deletion mouse models and ex vivo cultured organoids, we find that LSR elimination in intestinal stem cells results in disappearance of Paneth cell without affecting the differentiation of other cell lineages. Mechanistic studies reveal that LSR deficiency increase abundance and nuclear localization of YAP by modulating its phosphorylation and proteasomal degradation. Intestinal LSR-deficient mice are susceptible to development of necrotizing enterocolitis. In addition, LSR can sense and interpret fatty acid signals derived from dietary lipids and transduce into inactivation of YAP. Thus, this study identifies LSR as an upstream negative regulator of YAP activity and part of the mechanism mediating connection between fat diet and YAP signaling in intestine.

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“…Following all imaging studies in both healthy and NEC animal cohorts at the 4-day old timepoint, intestinal tissues were collected and processed for histological analysis along the entire ileal length, designated as the distal third of the total small intestinal length, as described in our prior study [28]. Hematoxylin and eosin (H&E) staining was performed on 4-μm thick sections containing cross-sections of the entire ileal length and were imaged at 10X using an EVOS FL Auto 2 Cell Imaging System (Invitrogen, CA).…”

Section: Methodsmentioning

confidence: 99%

“…Hematoxylin and eosin (H&E) staining was performed on 4-μm thick sections containing cross-sections of the entire ileal length and were imaged at 10X using an EVOS FL Auto 2 Cell Imaging System (Invitrogen, CA). H&E stained sections from each animal were graded for intestinal damage according to a histological NEC damage grade severity scoring system, as used in our prior study [28], with 0 designated as normal, 1 as disarrangement of villus cells with mild villus core separation, 2 as disarrangement of villus cells with severe villus core separation, 3 as epithelial sloughing, and 4 as bowel necrosis or perforation. The extent of ileal involvement of each NEC grade was serially assessed along 2-3 cm ileum length segments and the total ileal involvement for each NEC grade was calculated as the total linear length of ileum with each NEC grade, normalized by the total linear length of the ileum.…”

Section: Methodsmentioning

confidence: 99%

Photoacoustic Imaging for Non-Invasive Assessment of Physiological Biomarkers of Intestinal Injury in Experimental Necrotizing Enterocolitis

Weis,

Rauh,

Ellison

et al. 2023

Preprint

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Background: Necrotizing enterocolitis (NEC) is an often-lethal disease of the premature infants' intestinal tract that is exacerbated by significant difficulties in early and accurate diagnosis. In NEC disease, the intestine often exhibits hypoperfusion and dysmotility, which contributes to advanced disease pathogenesis. However, these physiological features cannot be accurately and quantitively assessed within the current constraints of imaging modalities frequently used in the clinic (plain film X-ray and ultrasound). We have previously demonstrated the ability of photoacoustic imaging (PAI) to non-invasively and quantitively assess intestinal tissue oxygenation and motility in a healthy neonatal rat model. As a first-in-disease application, we evaluated NEC pathogenesis using PAI to assess intestinal health biomarkers in a preclinical neonatal rat experimental model of NEC. Methods: NEC was induced in neonatal rat pups from birth to 4 days old via hypertonic formula feeding, full-body hypoxic stress, and lipopolysaccharide administration to mimic bacterial colonization. Healthy breastfed (BF) controls and NEC rat pups were imaged at 2- and 4-days old. Intestinal tissue oxygen saturation was measured with PAI imaging for oxy- and deoxyhemoglobin levels. To measure intestinal motility, ultrasound and co-registered PAI cine recordings were used to capture intestinal peristalsis motion and contrast agent (indocyanine green) transit within the intestinal lumen. Additionally, both midplane two-dimensional and volumetric three-dimensional imaging acquisitions were assessed for oxygenation and motility. Results: NEC pups showed a significant decrease of intestinal tissue oxygenation as compared to healthy BF controls at both ages (2-days old: 55.90% +/- 3.77% vs 44.12% +/- 7.18%; 4-days old: 56.13% +/- 3.52% vs 38.86% +/- 8.33%). Intestinal motility, assessed using a computational intestinal deformation analysis, demonstrated a significant reduction in the intestinal motility index in both early (2-day) and established (4-day) NEC. Extensive NEC damage was confirmed with histology and dysmotility was confirmed by small intestinal transit assay. Conclusions: This study presents PAI as a successful emerging diagnostic imaging modality for both intestinal tissue oxygenation and intestinal motility disease hallmarks in a rat NEC model. PAI presents enormous significance and potential for fundamentally changing current clinical paradigms for detecting and monitoring intestinal pathologies in the premature infant.

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Human placental-derived stem cell therapy ameliorates experimental necrotizing enterocolitis

Cited by 20 publications

References 87 publications

Gut-Brain cross talk: The pathogenesis of neurodevelopmental impairment in necrotizing enterocolitis

Gut-Brain cross talk: The pathogenesis of neurodevelopmental impairment in necrotizing enterocolitis

LSR Targets YAP to Modulate Intestinal Paneth Cell Differentiation

Photoacoustic Imaging for Non-Invasive Assessment of Physiological Biomarkers of Intestinal Injury in Experimental Necrotizing Enterocolitis

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