Human tissue-engineered small intestine forms from postnatal progenitor cells

Levin, Daniel E.; Barthel, Erik R.; Speer, Allison L.; Sala, F.G.; Hou, Xiaogang; Torashima, Yasuhiro; Grikscheit, Tracy C.

doi:10.1016/j.jpedsurg.2012.10.029

Cited by 66 publications

(55 citation statements)

References 26 publications

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“…Human small intestinal samples were collected under a CHLA IRB-approved protocol. Human ileum or mouse full-length small intestine tissue was washed in 4°C Hank's balanced salt solution; tissue digestion, OU preparation, polymer preparation, and implantation were then carried out using the established protocol previously validated and published by our group (3,21,27). Host animals were C57BL/6 for mouse OU implantation and adult Non-Obese Diabetic/Severe Combined ImmunoDeficiency (NOD/SCID) gamma mice (The Jackson Laboratories, Sacramento, CA) for human OU implantation.…”

Section: Methodsmentioning

confidence: 99%

“…Human intestine has the same regenerative potential. We previously demonstrated that TESI can be generated from human small intestine donor tissue implanted into immunocompromised host mice (2,21).…”

mentioning

confidence: 99%

“…Typical intracellular vacuoles can also be seen in secretory cells of the epithe-lium, representative of goblet cells. We previously published the identification of four terminally differentiated epithelial cell types in both mouse and human-derived TESI, including lysozyme-positive Paneth cells located at the crypt base, mucin-2 (Muc2)-positive goblet cells, apical villin-positive enterocytes, and enteroendocrine cells as identified by chromogranin A staining (21,27).…”

mentioning

confidence: 99%

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Human and mouse tissue-engineered small intestine both demonstrate digestive and absorptive function

Grant

Mojica

Sala

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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NC, Grikscheit TC. Human and mouse tissue-engineered small intestine both demonstrate digestive and absorptive function. Am J Physiol Gastrointest Liver Physiol 308: G664 -G677, 2015. First published January 8, 2015; doi:10.1152/ajpgi.00111.2014.-Short bowel syndrome (SBS) is a devastating condition in which insufficient small intestinal surface area results in malnutrition and dependence on intravenous parenteral nutrition. There is an increasing incidence of SBS, particularly in premature babies and newborns with congenital intestinal anomalies. Tissue-engineered small intestine (TESI) offers a therapeutic alternative to the current standard treatment, intestinal transplantation, and has the potential to solve its biggest challenges, namely donor shortage and life-long immunosuppression. We have previously demonstrated that TESI can be generated from mouse and human small intestine and histologically replicates key components of native intestine. We hypothesized that TESI also recapitulates native small intestine function. Organoid units were generated from mouse or human donor intestine and implanted into genetically identical or immunodeficient host mice. After 4 wk, TESI was harvested and either fixed and paraffin embedded or immediately subjected to assays to illustrate function. We demonstrated that both mouse and human tissue-engineered small intestine grew into an appropriately polarized sphere of intact epithelium facing a lumen, contiguous with supporting mesenchyme, muscle, and stem/progenitor cells. The epithelium demonstrated major ultrastructural components, including tight junctions and microvilli, transporters, and functional brush-border and digestive enzymes. This study demonstrates that tissue-engineered small intestine possesses a well-differentiated epithelium with intact ion transporters/channels, functional brush-border enzymes, and similar ultrastructural components to native tissue, including progenitor cells, whether derived from mouse or human cells. tissue engineering; regenerative medicine; intestinal failure; intestinal stem cell; short bowel syndrome PATIENTS WITH INTESTINAL FAILURE (IF) lose nutritional autonomy secondary to a broad range of metabolic and physiological disturbances, including fluid, nutrient, and weight loss secondary to insufficient intestinal surface area (10). Short bowel syndrome (SBS) is a major cause of IF and generally occurs with loss of ϳ50 -75% of small intestinal length (33). Congenital anomalies and perinatal disorders of the small intestine, such as gastroschisis, intestinal atresia, malrotation with volvulus, and necrotizing enterocolitis, may lead to SBS in children (32), whereas trauma and intestinal ischemia from fixation within an internal hernia following gastric bypass surgery are leading causes of SBS in adults. A 2004 study found an incidence of 22.1/1,000 neonatal intensive care unit admissions and a population estimate of 24.5/100,000 live births (35). The incidence of SBS is increasing, and morbidity and cost remain high, with a 30% 5-yr ...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Human and mouse tissue-engineered small intestine both demonstrate digestive and absorptive function

Grant

Mojica

Sala

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…An example of this is supported in a study by Lahar et al (52), which demonstrated that long-term culture of the human small intestinal epithelium required the presence of sub-epithelial myofibroblasts, even when exposed to Wnt3a-containing media. More recently, the Grikscheit laboratory, expanding upon the techniques developed by Evans et al (53) and Vacanti et al (54) in the rat, demonstrated successful regeneration of the human small intestine (termed tissue-engineered small intestine or TESI) from collagenase-digested "organoid units" that contain LGR5 ϩ stem cells and mesenchyme (55). Tissue-engineered small intestine exhibits a villus/crypt axis, but unlike intestinal organoids, it also contains enteric neurons, perhaps paving the way for neuronal cell replacement therapy in Hirschsprung disease (56).…”

Section: Intestinal Organogenesismentioning

confidence: 99%

Human Enteroids/Colonoids and Intestinal Organoids Functionally Recapitulate Normal Intestinal Physiology and Pathophysiology

Zachos¹,

Kovbasnjuk²,

Foulke‐Abel³

et al. 2016

Journal of Biological Chemistry

248

233

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Identification of Lgr5 as the intestinal stem cell marker as well as the growth factors necessary to replicate adult intestinal stem cell division has led to the establishment of the methods to generate "indefinite" ex vivo primary intestinal epithelial cultures, termed "mini-intestines." Primary cultures developed from isolated intestinal crypts or stem cells (termed enteroids/ colonoids) and from inducible pluripotent stem cells (termed intestinal organoids) are being applied to study human intestinal physiology and pathophysiology with great expectations for translational applications, including regenerative medicine. Here we discuss the physiologic properties of these cultures, their current use in understanding diarrhea-causing hostpathogen interactions, and potential future applications.

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“…Neurons, muscle cells and myofibroblasts were also observed (Grikscheit et al 2004). Additionally, the Sala laboratory succeeded in developing TESI in a pig model using OUs (Levin et al 2013). Furthermore, MSCs seeded on collagen scaffolds can regenerate into intestinal tissue; however, these MSCs failed to form a muscle layer as well as a mucosal layer formed by the migration of epithelial cells from the surrounding healthy intestinal mucosa (Gupta et al 2006).…”

Section: Tissue-engineered Small Intestine (Tesi)mentioning

confidence: 99%

Intestinal stem cells and stem cell-based therapy for intestinal diseases

2014

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Currently, many gastrointestinal diseases are a major reason for the increased mortality rate of children and adults every year. Additionally, these patients may cope with the high cost of the parenteral nutrition (PN), which aids in the long-term survival of the patients. Other treatment options include surgical lengthening, which is not sufficient in many cases, and intestinal transplantation. However, intestinal transplantation is still accompanied by many challenges, including immune rejection and donor availability, which may limit the transplant's success. The development of more safe and promising alternative treatments for intestinal diseases is still ongoing. Stem cell-based therapy (SCT) and tissue engineering (TE) appear to be the next promising choices for the regeneration of the damaged intestine. However, suitable stem cell source is required for the SCT and TE process. Thus, in this review we discuss how intestinal stem cells (ISCs) are a promising cell source for small intestine diseases. We will also discuss the different markers were used to identify ISCs. Moreover, we discuss the dominant Wnt signaling pathway in the ISC niche and its involvement in some intestinal diseases. Additionally, we discuss ISC culture and expansion, which are critical to providing enough cells for SCT and TE. Finally, we conclude and recommend that ISC isolation, culture and expansion should be considered when SCT is a treatment option for intestinal disorders. Therefore, we believe that ISCs should be considered a cell source for SCT for many gastrointestinal diseases and should be highlighted in future clinical applications.

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Human tissue-engineered small intestine forms from postnatal progenitor cells

Cited by 66 publications

References 26 publications

Human and mouse tissue-engineered small intestine both demonstrate digestive and absorptive function

Human and mouse tissue-engineered small intestine both demonstrate digestive and absorptive function

Human Enteroids/Colonoids and Intestinal Organoids Functionally Recapitulate Normal Intestinal Physiology and Pathophysiology

Intestinal stem cells and stem cell-based therapy for intestinal diseases

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