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PubMed2006

Optical tissue window: a novel model for optimizing engraftment of intestinal stem cell organoids.

BACKGROUND: Intestinal malabsorption disorders and short bowel syndrome lead to significant morbidity. We recently demonstrated that grafting of intestinal organoids can grow a bioengineered intestinal neomucosa and cure bile acid malabsorption in rats. Now we have developed a novel system that permits direct observation of intestinal organoids in vivo to optimize conditions for engraftment. METHODS: Optical Windows were created in C57BL/6J mice by externalizing an omental pedicle into a dorsal skin flap chamber. Following creation of windows, 5000 intestinal organoids from green-fluorescent protein transgene (GFP)+ donor mice were seeded directly either on omentum or on polyglycolic acid (PGA) disks that had been placed on omentum at 1 or 5 days. Engraftment of green fluorescent cells was evaluated on postseeding days 1, 3, 5, 7, 10, 12, and 21 using fluorescence microscopy. RESULTS: An initial group had seeding onto omentum (n = 5) or biopolymer disks (n = 5) on postoperative day 1. After 7 days, there was mucosal cell engraftment onto omental tissue and biopolymers. GFP+ organoids engrafted significantly better when seeded onto biopolymers compared to omentum (P < 0.05). In a second study with increased sample size (n = 24) up to day 12, all four groups demonstrated adherence and growth. However, GFP+ organoids seeded onto delayed PGA biopolymer demonstrated significantly better engraftment (P < 0.05). CONCLUSIONS: This novel system allows continuous in vivo observation of engrafted cells that are seeded on externalized omentum. The use of PGA mesh biopolymer may improve engraftment of intestinal organoids.

Animals↗
PubMed1994

Colonic mucosal replacement by syngeneic small intestinal stem cell transplantation.

A novel method of colonic mucosal replacement by transplantation of disaggregated small intestinal epithelium is described. Thirty-one inbred rats had the ascending colon isolated, and surgical mucosectomy was performed on the "free" loop. Epithelial cell aggregates were isolated from postnatal small intestine using collagenase and dispase digestion, then 20 microL of the cell suspension was "seeded" over the denuded colonic muscle of 25 recipient rats. Six control rats had surgical mucosectomy only. All loops were retrieved after 14 days for histologic examination. Stem cell lineage studies were used with selective staining protocols to identify enterocytes, goblet cells, entero-endocrine cells, and Paneth cells. A neomucosa with typical small bowel morphology including crypts and villi and all four stem cell lineages was regenerated by transplanted cells on the colonic muscle in 19 of 25 (76%) recipients. Control loops showed no epithelial regrowth confirming total mucosectomy. With appropriate stromal support, transplanted small intestinal stem cells have the capacity to re-epithelialize denuded colonic muscle with small bowel neomucosa.

Animals↗
PubMed2003

Intestinal stem cells and mucosal gut development.

PURPOSE OF REVIEW: In the past year, the study of intestinal stem cell biology has realized significant progress toward understanding the mechanisms and pathways regulating crypt stem cell turnover, maintenance, and differentiation. RECENT FINDINGS: This review summarizes recent investigations that have contributed significantly to the elucidation of mechanisms operative during intestinal development and in the adult intestine that regulate maintenance of the stem cell niche, cell fate and lineage allocation, and establishment and maintenance of the architectural organization of the crypt-to-villus axis. SUMMARY: The relevance of the findings discussed in this review extends beyond the field of intestinal development to encompass the study of tissue remodeling and repair and intestinal neoplasia.

Journal Article↗
PubMed2006

Gastric-and-intestinal mixed-type intestinal metaplasia: aberrant expression of transcription factors and stem cell intestinalization.

Helicobacter pylori plays a causative role in the development of chronic atrophic gastritis, intestinal metaplasia (IM), and stomach cancer. Although IM has long attracted attention as a putative preneoplastic lesion for stomach cancers, its clinicopathologic significance has yet to be clarified in detail. Using gastric and intestinal epithelial cell markers, IM was here divided into two major types: a gastric-and-intestinal (GI) mixed type and a solely intestinal (I) type. In the former, gastric and intestinal phenotypic markers appeared not only at the glandular but also at the cellular level. Furthermore, neuroendocrine cells also showed intestinalization along with their exocrine counterparts. In animal models, GI-type IM was found to appear first, followed by the solely I type. Summarizing these data, it was suggested that IM might be caused by the gradual intestinalization of stem cells from the GI to the I type. The molecular mechanisms of IM include the ectopic expression of CDX1, CDX2, OCT-1, and members of the Erk pathway. Suppression of the expression of gastric transcription factors such as SOX2, genes that are involved in the Sonic hedgehog pathway, and RUNX3, a tumor suppressor gene, could be additional relevant alterations. The expression of PDX1 may also be associated with pseudopyloric gland metaplasia and IM. Detailed analysis of gene regulation may shed light on the molecular bases of gastric lesions, leading to strategies for chemoprevention.

Animals↗
PubMed2005

Cellular and molecular regulation of hematopoietic and intestinal stem cell behavior.

Two fundamental questions in stem cell research are what controls stem cell number in vivo and which signal pathways regulate self-renewal. Here we summarize our recent studies regarding the role of BMP signaling in regulation of stem cell behavior in both the hematopoietic and intestinal systems. These studies provide evidence to show that BMP signaling plays an important role in controlling stem cell number, at least in these two stem cell compartments. However, the BMP signal utilizes different mechanisms to fulfill this purpose: in the hematopoietic stem cell compartment it controls stem cell number through regulation of the niche size; in the intestinal stem cell compartment it directly controls self-renewal of stem cells through restriction of Wnt/beta-catenin activity. The Bmpr1a mutant mouse provided an elegant model which allowed us to identify the HSC niche, an enigma for more than 25 years. Our work provided more evidence to demonstrate the essential function of the niche in maintenance of stem cells and showed that multiple signals are required to maintain a balanced control of stem cell self-renewal.

Animals↗
PubMed1992

Studies of intestinal stem cells using normal, chimeric, and transgenic mice.

The mouse intestinal epithelium represents a continuous developmental system. Its four principal differentiated cell types--enterocytes, goblet, enteroendocrine, and Paneth cells--are derived from a common multipotent stem cell located near the base of monoclonal crypts. Members of these four lineages undergo rapid and perpetual renewal along an anatomically well-defined pathway. The gut epithelium provides a unique mammalian model for studying the biological features of stem cells (e.g., their ability to undergo asymmetric division, their enormous proliferative potential, their capacity for functional anchorage in a niche), examining how stem cell hierarchies are established and maintained in renewing cell populations, analyzing the relationships between passage through the cell cycle and lineage allocation (commitment), and defining the mechanisms that give stem cells a "positional address" along the cephalocaudal axis, allowing them to generate regional differences in the differentiation programs of their derived lineages (axial pattern formation).

Animals↗
PubMed1979

The effect of lucanthone on the radiation response of intestinal stem cells in Chinese hamsters.

Crypt microcolony assay was used to determine the effect of lucanthone on the radiation response of intestinal stem cells in Chinese hamsters . The Dq of the crypt microcolony radiation--survival curve was maximally reduced by 205 rads when lucanthone injection preceded irradiation by 10 hours and was reduced by 140 rads when injection followed irradiation by 5 hours. On simultaneous injection and irradiation, Dq was reduced by only 20 rads; when injection and irradiation were separated by approximately 30 hours, Dq returned to the control value. Lucanthone never affected Do. Thus at non-toxic concentrations, lucanthone reversibly modifies cellular ability to accumulate and repair sublethal radiation damage without affecting radiation sensitivity.

Animals↗
PubMed1983

16, 16-dimethyl prostaglandin E2 increases survival of murine intestinal stem cells when given before photon radiation.

A variety of prostaglandins (PG) protect the gastric and intestinal mucosa when given before damaging agents such as absolute ethanol, acidified taurocholate, boiling water, or nonsteroidal anti-inflammatory agents (NSAI). A synthetic prostaglandin, 16, 16-dimethyl PGE2, shown to be cytoprotective at physiologic levels to the above agents was given to mice 1 hr before or 15 min after 137Cs gamma (gamma) whole-body irradiation. The survival of intestinal stem cells measured by their ability to form in situ colonies of regenerating epithelium was increased when 16, 16-dimethyl PGE2 was given before but not after 137Cs gamma irradiation. The maximum degree of 16, 16-dimethyl PGE2-induced radioprotection was seen when the drug was given 1 hr before irradiation. No radioprotection was seen when the interval between drug and irradiation was 3 hr or longer. When the time between 16, 16-dimethyl PGE2 and irradiation was kept at 1 hr, the degree of radioprotection was dependent on the PG drug dose. There was a steep rise in the number of surviving cells at low doses of PG. These results imply that tumors which secrete PGE2 may in part be protected from the lethal effects of ionizing photon radiation.

16,16-Dimethylprostaglandin E2↗
PubMed2003

Identification of a putative intestinal stem cell and early lineage marker; musashi-1.

There are few reliable markers for adult stem cells and none for those of the intestinal epithelium. Previously, indirect experimental approaches have predicted stem cell position and numbers. The Musashi-1 (Msi-1) gene encodes an RNA binding protein associated with asymmetric divisions in neural progenitor cells. Two-day-old, adult, and 4.5 h, 1-, 2-, 4- and 12-day post-irradiation samples of BDF1 mouse small intestine, together with some samples of mouse colon were stained with a rat monoclonal antibody to Musashi-1 (14 H-1). Min ( + / - ) mice with small intestinal adenomas of varying sizes were also analysed. Samples of human small and large bowel were also studied but the antibody staining was weak. Musashi-1 expression was observed using immunohistochemistry in neonatal, adult, and regenerating crypts with a staining pattern consistent with the predicted number and distribution of early lineage cells including the functional stem cells in these situations. Early dysplastic crypts and adenomas were also strongly Musashi-1 positive. In situ hybridization studies showed similar expression patterns for the Musashi mRNA and real-time quantitative RT-PCR showed dramatically more Msi-1 mRNA expression in Min tumours compared with adjacent normal tissue. These observations suggest that Musashi-1 is a marker of stem and early lineage progenitor cells in murine intestinal tissue.

Adult↗
PubMed2026

Co-targeting Deregulated WNT and MAPK Signaling Pathways Limits Phenotypic Reprogramming of Intestinal Stem Cell Progeny in KRAS-Hyperactivated Colorectal Cancer.

In their recent article, Moore and colleagues demonstrate that, upon KRAS hyperactivation, colorectal cancer growth is driven by a reprogramming of Lgr5+ intestinal stem cell (ISC) progeny towards the acquisition of a regenerative phenotype. They find that this phenotype is regulated by a balance between WNT-related ISCs and MAPK-related regenerative and proliferative transcriptional programs. By targeting both pathways, they are able to suppress this dynamic plasticity and achieve tumor regression in cell line and mouse models. The antagonistic relationship between these central pathways defined here provides key insights into genomic patterns of colorectal cancer and targeted therapy strategies.

Colorectal Neoplasms↗
PubMed2002

Intestinal stem cells protect their genome by selective segregation of template DNA strands.

The stem cells in the crypts of the small intestinal mucosa divide about a thousand times during the lifespan of a laboratory mouse, and yet they show little evidence of any decline in proliferative potential and rarely develop carcinogenic mutations, suggesting that their genome is extremely well protected. Protection against DNA-replication-induced errors can be achieved by the selective sorting of old (template) and new DNA strands with all template strands retained in the stem cell line. The template strands in the stem cells can be labelled during development or during tissue regeneration using tritiated thymidine ((3)HTdR). Labelling newly synthesised strands with a different marker (bromodeoxyuridine, BrdUrd) allows segregation of the two markers to be studied. Template strand label is retained ((3)HTdR), whereas label in the newly synthesised strands (BrdUrd) is lost following the second division of the stem cell. Random errors may occur in the template strands owing to environmental elements. These are protected against by the altruistic cell suicide (apoptosis) of the cells incurring such errors. A final level of protection for the tissue compensates for excessive deletion of stem cells via the apoptosis pathway. This is achieved by a hierarchical age structure in the stem cell compartment, with some cells being able to efficiently repair DNA damage and hence being more radioresistant. The presence of these protective mechanisms ensures that the small intestine rarely develops cancer and that stem cells can sustain the extensive cell proliferation needed during life.

Animals↗
PubMed1994

Novel delivery system for inducing quiescence in intestinal stem cells in rats by transforming growth factor beta 1.

BACKGROUND/AIMS: Intestinal mucosa, a tissue in a dynamic state of rapid cellular proliferation, is often adversely affected by cytotoxic drugs. The purpose of this study was to develop an oral delivery system targeting transforming growth factor (TGF) beta 1 locally and analyze its effects on the epithelial stem cells of gastrointestinal mucosa. METHODS: Rats were treated with recombinant TGF-beta 1 in alginate beads perorally or with recombinant TGF-beta 1 in phosphate-buffered saline perorally or intraperitoneally. Control animals received phosphate-buffered saline only. The size of the villi was measured. Proliferating and mitotic indices were determined by quantifying immunohistochemical staining for proliferating cell nuclear antigen. RESULTS: Alginate beads released no TGF-beta 1 in acid. However, in pH 7.4, TGF-beta 1 was released in an active form. Histomorphometrical analysis showed a marked reduction in villus height (50%-70%) in the intestinal mucosa of animals treated perorally with recombinant TGF-beta 1 in alginate beads. Also, the proliferating and mitotic indices were significantly reduced (P < 0.01) in these animals as compared with controls and other routes of administration. CONCLUSIONS: This study shows that recombinant TGF-beta 1 administered using a novel oral delivery system induces stem cell quiescence in the intestinal mucosa of the rat.

Administration, Oral↗
PubMed1991

Interleukin 1 beta initially sensitizes and subsequently protects murine intestinal stem cells exposed to photon radiation.

Interleukin 1 (IL-1) has been shown to prevent early bone marrow-related death following total-body irradiation, by protecting hematopoietic stem cells and speeding marrow repopulation. This study assesses the effect of IL-1 on the radiation response of the intestinal mucosal stem cell, a nonhematopoietic normal cell relevant to clinical radiation therapy. As observed with bone marrow, administration of human recombinant IL-1 beta (4 micrograms/kg) to C3H/Km mice 20 h prior to total-body irradiation modestly protected duodenal crypt cells. In contrast to bone marrow, IL-1 given 4 or 8 h before radiation sensitized intestinal crypt cells. IL-1 exposure did not substantially alter the slope of the crypt cell survival curve but did affect the shoulder: the X-ray survival curve was offset to the right by 1.01 +/- 0.06 Gy when IL-1 was given 20 h earlier and by 1.28 +/- 0.08 Gy to the left at the 4-h interval. Protection was greatest when IL-1 was administered 20 h before irradiation, but minimal effects persisted as long as 7 days after a single injection. The magnitude of radioprotection at 20 h or of radiosensitization at 4 h increased rapidly as IL-1 dose increased from 0 to 4 micrograms/kg. However, doses ranging from 10 to 100 micrograms/kg produced no further difference in radiation response. Animals treated with saline or IL-1 had similar core temperatures from 4 to 24 h after administration, suggesting that thermal changes were not responsible for either sensitization or protection. Mice irradiated 20 h after IL-1 had significantly greater crypt cell survival than saline-treated irradiated controls at all assay times, which ranged from 54 to 126 h following irradiation. The intervals to maximum crypt depopulation and initiation of repopulation were identical in both saline- and IL-1-treated groups, suggesting that IL-1 altered absolute stem cell survival but not the kinetics of repopulation.

Animals↗
PubMed1999

FGF-2 enhances intestinal stem cell survival and its expression is induced after radiation injury.

Fibroblast growth factors (FGFs) have mitogenic activity toward a wide variety of cells of mesenchymal, neuronal, and epithelial origin and regulate events in normal embryonic development, angiogenesis, wound repair, and neoplasia. FGF-2 is expressed in many normal adult tissues and can regulate migration and replication of intestinal epithelial cells in culture. However, little is known about the effects of FGF-2 on intestinal epithelial stem cells during either normal epithelial renewal or regeneration of a functional epithelium after injury. In this study, we investigated the expression of FGF-2 in the mouse small intestine after irradiation and determined the effect of exogenous FGF-2 on crypt stem cell survival after radiation injury. Expression of FGF-2 mRNA and protein began to increase at 12 h after gamma-irradiation, and peak levels were observed from 48 to 120 h after irradiation. At all times after irradiation, the higher molecular mass isoform ( approximately 24 kDa) of FGF-2 was the predominant form expressed in the small intestine. Immunohistochemical analysis of FGF-2 expression after radiation injury demonstrated that FGF-2 was predominantly found in the mesenchyme surrounding regenerating crypts. Exogenous recombinant human FGF-2 (rhFGF-2) markedly enhanced crypt stem cell survival when given before irradiation. We conclude that expression of FGF-2 is induced by radiation injury and that rhFGF-2 can enhance crypt stem cell survival after subsequent injury.

Animals↗
PubMed1997

Pretreatment with transforming growth factor beta-3 protects small intestinal stem cells against radiation damage in vivo.

The gastrointestinal tract, with its rapid cell replacement, is sensitive to cytotoxic damage and can be a site of dose-limiting toxicity in cancer therapy. Here, we have investigated the use of one growth modulator to manipulate the cell cycle status of gastrointestinal stem cells before cytotoxic exposure to minimize damage to this normal tissue. Transforming growth factor beta-3 (TGF-beta3), a known inhibitor of cell cycle progression through G1, was used to alter intestinal crypt stem cell sensitivity before 12-16 Gy of gamma irradiation, which was used as a model cytotoxic agent. Using a crypt microcolony assay as a measure of functional competence of gastrointestinal stem cells, it was shown that the administration of TGF-beta3 over a 24-h period before irradiation increased the number of surviving crypts by four- to six-fold. To test whether changes in crypt survival are reflected in the well-being of the animal, survival time analyses were performed. After 14.5 Gy of radiation, only 35% of the animals survived within a period of about 12 days, while prior treatment with TGF-beta3 provided significant protection against this early gastrointestinal animal death, with 95% of the treated animals surviving for greater than 30 days.

Animals↗
PubMed2004

BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling.

In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome, juvenile intestinal polyposis and Cowden disease, respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways. The mechanistic link between BMP and PTEN pathways and the related etiology of juvenile polyposis is unresolved. Here we show that conditional inactivation of Bmpr1a in mice disturbs homeostasis of intestinal epithelial regeneration with an expansion of the stem and progenitor cell populations, eventually leading to intestinal polyposis resembling human juvenile polyposis syndrome. We show that BMP signaling suppresses Wnt signaling to ensure a balanced control of stem cell self-renewal. Mechanistically, PTEN, through phosphatidylinosital-3 kinase-Akt, mediates the convergence of the BMP and Wnt pathways on control of beta-catenin. Thus, BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number.

Adenomatous Polyposis Coli↗
PubMed2006

Azoxymethane protects intestinal stem cells and reduces crypt epithelial mitosis through a COX-1-dependent mechanism.

Azoxymethane (AOM) is a potent DNA-damaging agent and carcinogen that induces intestinal and colonic tumors in rodents. Evaluation of the stem cell population by colony formation assay reveals that, within 8 h after treatment, AOM (10 mg/kg) elicited a prosurvival response. In wild-type (WT) mice, AOM treatment induced a 2.5-fold increase in intestinal crypt stem cell survival. AOM treatment increased stem cell survival in cyclooxygenase (COX)-2(-/-) but not COX-1(-/-) mice, confirming a role of COX-1 in the AOM-induced increase in stem cell survival. COX-1 mRNA and protein expression as well as COX-1-derived PGE(2) synthesis were increased 8 h after AOM treatment. Immunohistochemical staining of COX-1 demonstrated expression of the enzyme in the crypt epithelial cells, especially in the columnar epithelial cells between the Paneth cells adjacent to the stem cell zone. WT mice receiving AOM exhibited increased intestinal apoptosis and a simultaneous reduction in crypt mitotic figures within 8 h of injection. There were no significant differences in baseline or AOM-induced intestinal epithelial apoptosis between WT and COX-1(-/-) mice, but there was a complete reversal of the AOM-mediated reduction in mitosis in COX-1(-/-) mice. This suggests that COX-1-derived PGE(2) may play a key role in the early phase of intestinal tumorigenesis in response to DNA damage and suggests that COX-1 may be a potential therapeutic target in this model of colon cancer.

Animals↗
PubMed2004

Teduglutide ([Gly2]GLP-2) protects small intestinal stem cells from radiation damage.

Glucagon-like peptide-2 and its dipeptidyl peptidase (DP-IV) resistant analogue teduglutide are trophic for the gastrointestinal epithelium. Exposure increases villus height and crypt size and results in increased overall intestinal weight. As these effects may be mediated through stimulation of the stem cell compartment, they may promote intestinal healing and act as potential anti-mucositis agents in patients undergoing cancer chemotherapy. A study was initiated to investigate the protective effects of teduglutide on the murine small intestinal epithelium following gamma-irradiation using the crypt microcolony assay as a measure of stem cell survival and functional competence. Teduglutide demonstrated intestinotrophic effects in both CD1 and BDF1 mouse strains. In BDF1 mice, subcutaneous injection of GLP-2 or teduglutide (0.2 mg/kg/day, b.i.d.) for 14 days increased intestinal weight by 28% and resulted in comparable increases in crypt size, villus height and area. Teduglutide given daily for 6 or 14 days prior to whole body, gamma-irradiation significantly increased crypt stem cell survival when compared with vehicle-treated controls. The mean levels of protection over a range of doses provided protection factors from 1.3 to 1.5. A protective effect was only observed when teduglutide was given before irradiation. These results suggest that teduglutide has the ability to modulate clonogenic stem cell survival in the small intestine and this may have a useful clinical application in the prevention of cancer therapy-induced mucositis.

Animals↗