Xenotransplantation of human intestine into mouse abdomen or subcutaneous tissue: Novel platforms for the study of the human enteric nervous system

Nagy, Nándor; Marsiano, Noga; Bruckner, Ramona S; Scharl, Michael; Gutnick, Michael J.; Arciero, Emily; Goldstein, Allan M.; Shpigel, Nahum Y.

doi:10.1111/nmo.13212

Cited by 10 publications

(13 citation statements)

References 14 publications

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“…While ectopic and not functional, these gut implants develop characteristic structures of the human gut with extensive vasculature and their structural features are highly similar to those of normal human gut, including mucosal villous epithelium, crypt structures, blood vessels and enteric nervous system. We and others have previously shown that virtually all the cell types that are present in the normal human gut are also present in these xenografts (Savidge et al, 1995;Savidge et al, 2001;Golan et al, 2009;Golan et al, 2011;Nissim-Eliraz et al, 2017;Nagy et al, 2018;Bruckner et al, 2019). Moreover, the general architecture of the gut appears normal, and the tissue is well-vascularized by a human capillary system that anastomoses to the circulatory system of the murine host.…”

Section: Ibdmentioning

confidence: 89%

“…We have examined the activation of NF-B in segments of human fetal gut transplanted and developing in a subcutaneous, sterile environment in SCID mice. The experimental model system we have used was first reported by Winter et al in 1991(Winter et al, 1991 and refined in our laboratories for study of the human enteric nervous system (Nagy et al, 2018), human-specific pathogens (Golan et al, 2009;Golan et al, 2011) and inflammatory bowel diseases (IBD) (Canavan et al, 2016;Bruckner et al, 2019;Goldberg et al, 2019). Fetal gut was obtained after informed consent from pregnancy terminations performed legally at 12-18 weeks gestational age and transplanted subcutaneously in mature SCID mice.…”

Section: Ibdmentioning

confidence: 99%

“…This model system was extensively described by us (Golan et al, 2009;Golan et al, 2011;Canavan et al, 2016;Nissim-Eliraz et al, 2017;Nagy et al, 2018;Bruckner et al, 2019;Goldberg et al, 2019). C.B-17/IcrHsd-Prkdc scid (abbreviated as SCID) mice were purchased from Harlan Biotech Israel (Rehovot, Israel).…”

Section: Scid Mouse Human Intestinal Xeno-transplant Modelsmentioning

confidence: 99%

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NF-kappa-B activation unveils the presence of inflammatory hotspots in human gut xenografts

Nissim-Eliraz

Nir

Marsiano

et al. 2020

Preprint

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The single-epithelial cell layer of the gut mucosa serves as an essential barrier between the host and luminal microflora and plays a major role in innate immunity against invading pathogens. Nuclear factor kB (NF-κB), a central component of the cellular signaling machinery, regulates immune response and inflammation. NF-κB proteins are activated by signaling pathways downstream to microbial recognition receptors and cytokines receptors. Highly regulated NF-κB activity in intestinal epithelial cells (IEC) is essential for normal gut homeostasis; dysregulated activity has been linked to a number of disease states, including inflammatory bowel diseases (IBD) such as Crohn’s Disease (CD). Our aim was to visualize and quantify spatial and temporal dynamics of NF-κB activity in steady state and inflamed human gut. Lentivirus technology was used to transduce the IEC of human gut xenografts in SCID mice with a NF-κB luminescence reporter system. NF-κB signaling was visualized and quantified using low resolution, intravital imaging of the whole body and high resolution, immunofluorescence microscopic imaging of the tissues. We show that NF-κB is activated in select subset of IEC with low “leaky” NF-κB activity. These unique inflammatory epithelial cells are clustered in the gut into discrete hotspots of NF-κB activity that are visible in steady state and selectively activated by systemic LPS and human TNFα or luminal bacteria. The presence of inflammatory hotspots in the normal and inflamed gut might explain the patchy mucosal lesions characterizing CD and thus could have important implications for diagnosis and therapy.

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Section: Ibdmentioning

confidence: 89%

Section: Ibdmentioning

confidence: 99%

Section: Scid Mouse Human Intestinal Xeno-transplant Modelsmentioning

confidence: 99%

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NF-kappa-B activation unveils the presence of inflammatory hotspots in human gut xenografts

Nissim-Eliraz

Nir

Marsiano

et al. 2020

Preprint

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“…It is known that there is some heterogeneity between different donors; for example, age, sex, body mass index, and site of harvest are known to have an effect on the properties of the ASCs [43][44][45][46][47]. Xenotransplantation has been used before to study development, physiology, and pathophysiology of human tissues in animal models, for example, enteric nervous system [48] and rodent models have been tested in treatment of stroke [49] and myocardial infarct [50]. However, there are differences in human and animal physiology that have to be kept in mind when interpreting the results [51].…”

Section: Discussionmentioning

confidence: 99%

Functional Outcome of Human Adipose Stem Cell Injections in Rat Anal Sphincter Acute Injury Model

Kuismanen

Juntunen

Narra

et al. 2018

Stem Cells Translational Medicine

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Anal incontinence is a devastating condition that significantly reduces the quality of life. Our aim was to evaluate the effect of human adipose stem cell (hASC) injections in a rat model for anal sphincter injury, which is the main cause of anal incontinence in humans. Furthermore, we tested if the efficacy of hASCs could be improved by combining them with polyacrylamide hydrogel carrier, Bulkamid. Human ASCs derived from a female donor were culture expanded in DMEM/F12 supplemented with human platelet lysate. Female virgin Sprague‐Dawley rats were randomized into four groups (n = 14–15/group): hASCs in saline or Bulkamid (3 × 105/60 μl) and saline or Bulkamid without cells. Anorectal manometry (ARM) was performed before anal sphincter injury, at two (n = 58) and at four weeks after (n = 33). Additionally, the anal sphincter tissue was examined by micro‐computed tomography (μCT) and the histological parameters were compared between the groups. The median resting and peak pressure during spontaneous contraction measured by ARM were significantly higher in hASC treatment groups compared with the control groups without hASCs. There was no statistical difference in functional results between the hASC‐carrier groups (saline vs. Bulkamid). No difference was detected in the sphincter muscle continuation between the groups in the histology and μCT analysis. More inflammation was discovered in the group receiving saline with hASC. The hASC injection therapy with both saline and Bulkamid is a promising nonsurgical treatment for acute anal sphincter injury. Traditional histology combined with the 3D μCT image data lends greater confidence in assessing muscle healing and continuity. Stem Cells Translational Medicine 2018;7:295–304

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“…While responses are simulated by tumor engraftment, alloresponses are simulated by engraftment of human cells or tissues; the most common models being those that engraft human skin, 86 islets of Langerhans, 87 or blood vessels. 88 The most widely used model is that of human skin allotransplantation. 89 - 93 Skin grafts benefit from tissue accessibility permitting continuous visible monitoring and from an established progression of rejection in skin architecture and leukocyte infiltration.…”

Section: Micementioning

confidence: 99%

Humanization of Immunodeficient Animals for the Modeling of Transplantation, Graft Versus Host Disease, and Regenerative Medicine

et al. 2020

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The humanization of animals is a powerful tool for the exploration of human disease pathogenesis in biomedical research, as well as for the development of therapeutic interventions with enhanced translational potential. Humanized models enable us to overcome biologic differences that exist between humans and other species, while giving us a platform to study human processes in vivo. To become humanized, an immune-deficient recipient is engrafted with cells, tissues, or organoids. The mouse is the most well studied of these hosts, with a variety of immunodeficient strains available for various specific uses. More recently, efforts have turned to the humanization of other animal species such as the rat, which offers some technical and immunologic advantages over mice. These advances, together with ongoing developments in the incorporation of human transgenes and additional mutations in humanized mouse models, have expanded our opportunities to replicate aspects of human allotransplantation and to assist in the development of immunotherapies. In this review, the immune and tissue humanization of various species is presented with an emphasis on their potential for use as models for allotransplantation, graft versus host disease, and regenerative medicine.

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Xenotransplantation of human intestine into mouse abdomen or subcutaneous tissue: Novel platforms for the study of the human enteric nervous system

Cited by 10 publications

References 14 publications

NF-kappa-B activation unveils the presence of inflammatory hotspots in human gut xenografts

NF-kappa-B activation unveils the presence of inflammatory hotspots in human gut xenografts

Functional Outcome of Human Adipose Stem Cell Injections in Rat Anal Sphincter Acute Injury Model

Humanization of Immunodeficient Animals for the Modeling of Transplantation, Graft Versus Host Disease, and Regenerative Medicine

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