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PubMed1982

Proliferative and morphological adaptation of the intestine to experimental resection.

The proliferative and morphological adaptation of the residual intestine following resection is briefly reviewed. Within days after a partial intestinal resection, the number of crypt cells increases. There is a proportional increase in the number of proliferative cells, thus there is no change in the growth fraction. Villus height and morphological complexity increases, particularly in the ileum. The thickness of the muscularis mucosae increases, most likely through an increase in cellularity. The size of the adaptive response is dependent on the amount of tissue removed. The possibility of an adaptive change in the number and proliferative characteristics of rat intestinal stem cells was investigated using the microcolony assay (38). Regenerative foci of mucosal epithelium were quantitated as a function of 137Cs gamma ray irradiation in control or 30 days after a 60% resection of the combined jejunum and ileum. Hydroxyurea, (HU), an S phase cytotoxic agent was given to one group of control and one group of resected rats five minutes before a single dose of radiation. HU had little effect on control jejunum or ileum, however, HU reduced the clonogenic cell survival by over tenfold in resected animals which implies a post-resection change in the intestinal stem cell age distribution. The radiation dose-survival curve of clonogenic cells was shifted to the right after resection compared to control values. These results suggest that an increase in intestinal stem cell number and a shift in the proliferative characteristics (from slowly to rapidly cycling) occur as an adaptive response to intestinal resection.

Adaptation, Physiological↗
PubMed2001

Regulation of human intestinal mast cells by stem cell factor and IL-4.

Mature human mast cells are tissue-residing, key effector cells of immediate allergic reactions. Moreover, mast cells have been recognized as a potent cellular source of multiple cytokines, suggesting an important role in immunoregulation and host defense. Here, we report on the regulation of mature human mast cells isolated from intestinal tissues by stem cell factor (SCF) and interleukin (IL)-4. SCF is substantially necessary for mast cell survival and induces marginal mast cell proliferation in vitro, whereas IL-4 by itself has no effects on mast cell survival or proliferation. Most interestingly, in synergy with SCF, IL-4 strongly enhances mast cell proliferation. In the presence of SCF, mast cells predominantly produce pro-inflammatory cytokines including tumor necrosis factor (TNF)-alpha, IL-1beta, IL-6, IL-8, IL-16, and IL-18. Addition of IL-4 to the culture medium induces the expression of Th2-type cytokines (IL-3, IL-5 and IL-13), and a downregulation of pro-inflammatory cytokines, namely IL-6. Furthermore, SCF by itself supports the predominance of the tryptase/chymase double-positive mast cell subtype MCTC whereas the addition of IL-4 supports the chymase negative MCT subtype. In conclusion, SCF may primarily regulate resident mast cell survival, whereas IL-4 may promote local proliferation of mast cells and their expression of Th2-type cytokines.

Cell Division↗
PubMed2002

Combined expression of pancreatic duodenal homeobox 1 and islet factor 1 induces immature enterocytes to produce insulin.

Immature rat intestinal stem cells (IEC-6) given the ability to express the transcription factor, pancreatic duodenal homeobox 1 (Pdx-1), yielded YK cells. Although these cells produced multiple enteroendocrine hormones, they did not produce insulin. Exposure of YK cells to 2 nmol/l betacellulin yielded BYK cells that showed the presence of insulin expression in cytoplasm and that secreted insulin into culture media. By examining the mechanism of differentiation in BYK cells, we found that another transcription factor, islet factor 1 (Isl-1) was newly expressed with the disappearance of Pax-6 expression in those cells after exposure to betacellulin. These results indicated that combined expression of Pdx-1 and Isl-1 in IEC-6 cells was required for the production of insulin. In fact, overexpression of both Pdx-1 and Isl-1 in IEC-6 cells (Isl-YK-12, -14, and -15 cells) gave them the ability to express insulin without exposure to betacellulin. Furthermore, implantation of the Isl-YK-14 cells into diabetic rats reduced the animals' plasma glucose levels; glucose levels dropped from 19.4 to 16.9 mmol/l 1 day after the injection of cells. As expected, the plasma insulin concentrations were 2.7 times higher in the diabetic rats injected with Isl-YK-14 cells compared to in controls. In summary, our results indicated that immature intestinal stem cells can differentiate into insulin-producing cells given the ability to express the transcription factors Pdx-1 and Isl-1.

Animals↗
PubMed1986

A comparison of radioprotection from three neutron sources and 60Co by WR-2721 and WR-151327.

Two thiophosphoroate radiation protectors (WR-2721 and WR-151327) were assessed for their ability to modify the effects of neutron or gamma irradiation on the gastrointestinal tract. Three neutron sources (DOSAR, JANUS, and FERMILAB) were compared to the response obtained after 60Co irradiation. The end points studied were intestinal stem cell survival and LD50(6). DOSAR and JANUS, both fission-spectrum neutrons, showed somewhat different gut sensitivities [LD50(6)] of about 240 and 400 cGy respectively. The intestinal LD50 obtained with FERMILAB neutrons (25 meV) was closer (875 cGy) to that obtained after 60Co (1068 cGy) irradiation. WR-151327 protected against the lethal effects of fission neutron (DOSAR and JANUS) to a greater degree (DMF = 2.2) than with lower LET sources such as FERMILAB neutrons (DMF = 1.7) or 60Co (DMF = 1.7). The results did not correlate with the intestinal stem cell assays where WR-2721 when compared to WR-151327 showed either similar (DOSAR; fission spectrum neutrons) or somewhat better (60Co and FERMILAB neutrons) protection. Possible explanations for the differing results are discussed.

Amifostine↗
PubMed1996

Protection of the small intestinal clonogenic stem cells from radiation-induced damage by pretreatment with interleukin 11 also increases murine survival time.

The effect of administering recombinant human interleukin 11 in conjunction with cytotoxic insults to the gastrointestinal tract has been studied using the crypt microcolony assay for stem cell function and whole-animal survival time studies. The cytotoxic regimens include single doses of gamma rays; single doses of 5-fluorouracil (5-FU) and multiple doses of 5-FU spaced 6 h apart. Interleukin 11 (IL-11) (100 micrograms/kg) delivered over a period of time prior to cytotoxic exposure afforded protection to the clonogenic cells in the crypts as seen with the microcolony assay and prolonged the animal survival time following radiation exposure. Continuing this dose of IL-11 after cytotoxic exposure afforded little additional protection. Three doses of 5-FU 6 h apart generated crypt survival curves similar to those obtained after a single dose of gamma rays. IL-11 given prior to two doses of 5-FU effectively abolished the cytotoxic effect of the second dose of 5-FU; i.e., 2.5-3.0 times more crypts survived if IL-11 was administered when the higher 5-FU doses are considered. IL-11 given before a dose of 12 Gy of gamma rays prolonged the survival time of animals by three to four days. This confirms earlier studies demonstrating that protecting clonogenic cells in the crypt survival assay can result in beneficial effects on whole-animal survival times.

Animals↗
PubMed2001

Protection against mucosal injury by growth factors and cytokines.

This article provides an overview of published studies in which growth factors and cytokines were used to modify the sensitivity of intestinal stem cells to a dose of radiation. In these experiments, growth factors were used to manipulate the sensitivity of stem cells in the gastrointestinal tract to reduce the severity of gastrointestinal mucositis in cancer therapy patients. Transforming growth factor beta3, interleukin 11, and keratinocyte growth factor were used. All three agents, given according to appropriate protocols, can result in a threefold to fourfold increase in the number of intestinal stem cells that survive a dose of radiation therapy. This result was assessed by using the crypt microcolony assay of stem cell functional capacity. The changes in stem cell survival that were observed resulted in increased animal survival. This increased survival was taken as a surrogate for improvement in patient well-being. The severity of diarrhea, a marker of functional impairment, was concomitantly reduced.

Animals↗
PubMed2006

Mechanisms of disease: from stem cells to colorectal cancer.

Over the past decade, the advances in our understanding of stem cell biology and the role of stem cells in diseases, such as colorectal cancer, have been remarkable. In particular, discoveries related to the control of stem cell proliferation and how dysregulation of proliferation leads to oncogenesis have been foremost. For intestinal stem cells, the WNT family of growth factors, and events such as the regulation of the nuclear localization of beta-catenin, seem to be central to normal homeostasis, and mutations in the components of these pathways seem to lead to the development of colorectal cancer. A paradigm of abnormal stem cell biology is illustrated by patients with familial adenomatous polyposis, who have mutations in the adenomatous polyposis coli gene. The wild-type protein encoded by this gene is important for the prevention of mass beta-catenin accumulation in the nucleus and the subsequent overtranscription of cell cycle proteins. This review discusses the basic mechanisms behind stem cell regulation in the gut and follows their role in the natural history of tumor progression.

Adenoma↗
PubMed1985

16,16-Dimethyl prostaglandin E2 induces radioprotection in murine intestinal and hematopoietic stem cells.

Exogenous prostaglandins (PGs) have been shown to protect gastrointestinal mucosa, liver, and pancreas from several injurious agents, including the PG inhibitor, indomethacin. Previous studies from this laboratory showed exogenous administration of 16,16-dimethyl (dm) PGE2 also protected mouse intestinal stem cells from radiation injury. The present study extended that observation and demonstrated that PGs given to B6D2F1 mice 1 hr before irradiation increased the shoulder of the intestinal clonogenic cell survival curve. The D0 increased from 1.10 + 0.09 to 1.58 + 0.10 Gy. PGs increased the LD50/6 from 16.3 + 0.41 (95% confidence limits) in controls to 20.25 + 0.55 Gy. The 16,16-dm PGE2 increased the hematopoietic CFU-S survival in a qualitatively similar way; the extrapolation number (n) was increased from 1.03 (0.89-1.20) to 1.40 (1.27-1.54) and the D0 increased from 0.92 (0.87-0.98) to 1.14 (1.10-1.19) Gy. A large number of human tumors secrete a variety of PGs. Our results suggest that those tumors may be, in part, protected from radiation injury.

16,16-Dimethylprostaglandin E2↗
PubMed2002

Prosurvival and antiapoptotic effects of PGE2 in radiation injury are mediated by EP2 receptor in intestine.

The biological activities of PGE(2) are mediated through EP receptors (EP(1)-EP(4)), plasma membrane G protein-coupled receptors that differ in ligand binding and signal-transduction pathways. We investigated gastrointestinal EP(2) receptor expression in adult mice before and after radiation injury and evaluated intestinal stem cell survival and crypt epithelial apoptosis after radiation injury in EP(2) null mice. EP(2) was expressed throughout the gut. Intestinal EP(2) mRNA increased fivefold after gamma-irradiation. Crypt survival was diminished in EP(2)-/- mice (4.06 crypts/cross section) compared with wild-type littermates (8.15 crypts/cross section). Radiation-induced apoptosis was significantly increased in EP(2)-/- mice compared with wild-type littermates. Apoptosis was 1.6-fold higher in EP(2) (-/-) mice (5.9 apoptotic cells/crypt) than in wild-type mice (3.5 apoptotic cells/crypt). The EP(2) receptor is expressed in mouse gastrointestinal epithelial cells and is upregulated following radiation injury. The effects of PGE(2) on both crypt epithelial apoptosis and intestinal crypt stem cell survival are mediated through the EP(2) receptor.

Animals↗
PubMed2005

Age-related human small intestine methylation: evidence for stem cell niches.

BACKGROUND: The small intestine is constructed of many crypts and villi, and mouse studies suggest that each crypt contains multiple stem cells. Very little is known about human small intestines because mouse fate mapping strategies are impractical in humans. However, it is theoretically possible that stem cell histories are inherently written within their genomes. Genomes appear to record histories (as exemplified by use of molecular clocks), and therefore it may be possible to reconstruct somatic cell dynamics from somatic cell errors. Recent human colon studies suggest that random somatic epigenetic errors record stem cell histories (ancestry and total numbers of divisions). Potentially age-related methylation also occurs in human small intestines, which would allow characterization of their stem cells and comparisons with the colon. METHODS: Methylation patterns in individual crypts from 13 small intestines (17 to 78 years old) were measured by bisulfite sequencing. The methylation patterns were analyzed by a quantitative model to distinguish between immortal or niche stem cell lineages. RESULTS: Age-related methylation was observed in the human small intestines. Crypt methylation patterns were more consistent with stem cell niches than immortal stem cell lineages. Human large and small intestine crypt niches appeared to have similar stem cell dynamics, but relatively less methylation accumulated with age in the small intestines. There were no apparent stem cell differences between the duodenum and ileum, and stem cell survival did not appear to decline with aging. CONCLUSION: Crypt niches containing multiple stem cells appear to maintain human small intestines. Crypt niches appear similar in the colon and small intestine, and the small intestinal stem cell mitotic rate is the same as or perhaps slower than that of the colon. Although further studies are needed, age-related methylation appears to record somatic cell histories, and a somatic epigenetic molecular clock strategy may potentially be applied to other human tissues to reconstruct otherwise occult stem cell histories.

Adolescent↗
PubMedDate not supplied

[Radiobiological aspects of increased radioresistance of murine epithelial stem cells from patches of Peyer].

The fraction of the survived intestinal crypts associated with patches of Peyer is higher to those non-patch-associated crypts of mice for three inbred strains. The difference in the survival between associated and non-patch-associated crypts increases with dose of gamma-irradiation. This difference for old mice is less than for young mice. Pre-irradiation (5 Gy) of mice one week before the conditioned gamma-irradiation cannot modify the difference in the survival between associated and non-patch-associated crypts. Radioprotection of mice by hypoxic gas mixture (10% O2) cannot modify this difference. Pre-treatment of mice by dextran-sulfate alone or in combination with hypoxic gas mixture decreased the survival of intestinal crypts associated with patches of Peyer to the level of non-path-associated crypts. The difference in the survival between two subpopulation of intestinal stem cells is less after neutron irradiation than after gamma-irradiation.

Aging↗
PubMed2004

Increased cell turnover, but no signs of increased T-cell infiltration or inflammatory cytokines in the duodenum of pediatric patients after allogeneic stem cell transplantation.

Intestinal immunopathology was studied after allogeneic stem cell transplantation (SCT) in a common clinical setup in 20 children with malignant (n=17) or nonmalignant diseases (n=3) receiving grafts from siblings (7) and unrelated donors (13). In all, 19 had total body irradiation. Duodenal biopsies at 6 and 12 weeks post transplant were evaluated by histology, immunohistochemistry, and ISEL for the detection of T-lymphocytes, inflammatory cytokines, proliferation, and apoptosis. The controls were 12 healthy children and three patients with proven intestinal graft-versus-host disease. An increased rate of apoptosis and proliferation with upregulated expression of HLA-DR antigen was detected up to 3 months post transplant in the SCT patients, even in those with a histologically normal small intestine. A low level of IFNgamma and TNFalpha was observed in the lamina propria. The initial low density of gammadelta-positive T cells had recovered to normal by the time of the second endoscopy at 12 weeks post transplant. We conclude that inflammatory activity and T cell infiltration detected by immunohistochemistry may not belong to the 'normal' recovery of the small intestine after SCT. Increased cell turnover in the intestinal crypts continues until 3 months after SCT, suggesting either an unexpectedly long-lasting effect of transplant-related toxicity or, preferably, an ongoing subclinical alloreactive process, also present in the patients without intestinal symptoms.

Adolescent↗
PubMed2005

Innate defenses of the intestinal epithelial barrier.

The innate immune system plays a crucial role in maintaining the integrity of the intestine and protecting the host against a vast number of potential microbial pathogens from resident and transient gut microflora. Mucosal epithelial cells and Paneth cells produce a variety of antimicrobial peptides (defensins, cathelicidins, crytdinrelated sequence peptides, bactericidal/permeabilityincreasing protein, chemokine CCL20) and bacteriolytic enzymes (lysozyme, group IIA phospholipase A2) that protect mucosal surfaces and crypts containing intestinal stem cells against invading microbes. Many of the intestinal antimicrobial molecules have additional roles of attracting leukocytes, alarming the adaptive immune system or neutralizing proinflammatory bacterial molecules. Dysfunction of components of the innate immune system has recently been implicated in chronic inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, illustrating the pivotal role of innate immunity in maintaining the delicate balance between immune tolerance and immune response in the gut.

Animals↗
PubMed1986

Effect of the interval between high dose 1-beta-D-arabinofuranosylcytosine injections on leukemic cell load, intestinal toxicity, and normal hematopoietic stem cells in a rat model for acute myelogenous leukemia.

One injection of 1-beta-D-arabinofuranosylcytosine (ara-C) in BN rats bearing myelocytic leukemia induces recruitment and synchronization of the leukemic cells. A second ara-C injection, given when the largest fraction of cells is in S phase, causes the largest reduction in leukemic clonogenic cells. The relevance of recruitment and synchronization of leukemic cells after high dose ara-C (200 mg/kg) by rapid i.v. injection (comparable with 1 g/m2 in patients) has been tested in rats with respect to survival time and toxicity. Several groups of leukemic rats have been treated with seven injections of ara-C; the intervals between the injections per group were 4, 6, 9, 12, 15, 18, and 24 h, respectively. The longest mean survival time is observed in the group treated every 9 h which is 70.8 days compared to 22.6 days in nontreated leukemic controls. This 9-h interval of ara-C administration corresponds with the moment when DNA synthesis of the leukemic cells resumes after its inhibition by the ara-C. The most severe toxic side effects on the gastrointestinal system are observed in the group that received ara-C every 6 h; no toxic death has occurred in the animals treated with 15-h or longer intervals. The effect of the increasing interval between two ara-C injections on the normal hematopoietic stem cells has been measured with the colony forming unit spleen assay. This study showed that the reduction of normal stem cells due to ara-C is independent of the interval of administration. This differential effect of ara-C on leukemic and normal hematopoietic stem cell kinetics might in part explain the mechanisms of achieving a complete remission in acute leukemia.

Animals↗
PubMed1986

A test of the stochastic theory of stem cell differentiation.

Stochastic theories of stem cell renewal are shown to predict turnover of intestinal crypts. While I found ample evidence of production of new crypts from direct in vivo studies in adult mice, I failed to find evidence of crypt loss. Thus, it would appear that the simple stochastic models may not provide an adequate theory of control of intestinal stem cell function.

Animals↗
PubMed2001

Gastrointestinal cells of IL-7 receptor null mice exhibit increased sensitivity to irradiation.

IL-7 is a critical cytokine in the development of T and B cells but little is known about its activity on nonhematopoietic cells. An unexpected finding was noted in allogeneic bone marrow transplant studies using IL-7 receptor null (IL-7R alpha(-/-)) mice as recipients. These mice exhibited a significantly greater weight loss after total body irradiation compared with wild type, IL-7R alpha(+/+), mice. Pathological assessment indicated greater intestinal crypt damage in IL-7R alpha(-/-) recipients, suggesting these mice may be predisposed to gut destruction. Therefore, we determined the effect of the conditioning itself on the intestinal tract of these mice. IL-7R alpha(-/-) mice and IL-7R alpha(+/+) mice were irradiated and examined for lesions and apoptosis within the small intestine. In moribund animals, IL-7R alpha(-/-) mice had extensive damage in the small intestine, including marked ablation of the crypts and extreme shortening of villi following 1500 cGy total body irradiation. In contrast, by 8 days after irradiation, the small intestines of IL-7R alpha(+/+) mice had regenerated as distinguished by normal villus length and hyperplastic crypts. Following 750 cGy irradiation, IL-7R alpha(-/-) mice had a higher proportion of apoptotic cells in the crypts and an accompanying increase in the pro-apoptotic protein Bak was expressed in intestinal epithelial cells. These results demonstrate the increased radiosensitivity of intestinal stem cells within the crypts in IL-7R alpha(-/-) mice and a role for IL-7 in the protection of radiation-induced apoptosis in these same cells. This study describes a novel role of IL-7 in nonhematopoietic tissues.

Animals↗
PubMed1991

A stochastic branching model with formation of subunits applied to the growth of intestinal crypts.

The intestinal epithelium is one of the most rapidly regenerating tissues in mammals. Cell production takes place in the intestinal crypts which contain about 250 cells. Only a minority of 1-60 proliferating cells are able to maintain a crypt over a long period of time. However, so far attempts to identify these stem cells were unsuccessful. Therefore, little is known about their cellular growth and selfmaintenance properties. On the other hand, the crypts appear to exhibit a life cycle which starts by fission of existing crypts and ends by fission or extinction. Data on these processes have recently become available. Here, we demonstrate how these data on the life cycle of the macroscopic crypt structure can be used to derive a quantitative model of the microscopic process of stem cell growth. The model assumptions are: (1) stem cells undergo a time independent supracritical Markovian branching process (Galton-Watson process); (2) a crypt divides if the number of stem cells exceeds a given threshold and the stem cells are distributed to both daughter crypts according to binomial statistics; (3) the size of the crypt is proportional to the stem cell number. This model combining two different stochastic branching processes describes a new class of processes whose stationary stability and asymptotic behavior are examined. This model should be applicable to various growth processes with formation of subunits (e.g. population growth with formation of colonies in biology, ecology and sociology). Comparison with crypt data shows that intestinal stem cells have a probability of over 0.8 of dividing asymmetrically and that the threshold number should be 8 or larger.

Animals↗