Epithelial Regeneration after Doxorubicin Arises Primarily from Early Progeny of Active Intestinal Stem Cells

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Available drugs aim to suppress gut inflammation. These drugs have significantly delayed disease progression and improved patients’ quality of life. However, the disease continues to progress, underscoring the need to develop novel therapies. Aside from chronic gut inflammation, IBD patients also experience a leaky gut problem due to damage to the intestinal epithelial layer. In this regard, epithelial regeneration and repair are mediated by intestinal stem cells. However, no therapies are available to directly enhance the intestinal stem cells’ regenerative and repair function. Recently, it was shown that active vitamin D, i.e., 1,25-dihydroxyvitamin D or 1,25(OH)2D, was necessary to maintain Lgr5+ intestinal stem cells, actively cycling under physiological conditions. In this study, we used two strategies to investigate the role of 1,25(OH)2D in intestinal stem cells’ regenerative function. First, to avoid the side effects of systemic high 1,25(OH)2D conditions, we used our recently developed novel strategy to deliver locally high 1,25(OH)2D concentrations specifically to inflamed intestines. Second, because of the Lgr5+ intestinal stem cells’ active cycling status, we used a pulse-and-chase strategy via 5-bromo-2′-deoxyuridine (BrdU) labeling to trace the Lgr5+ stem cells through the whole epithelial regeneration process. Our data showed that locally high 1,25(OH)2D concentrations enhanced intestinal stem cell migration. Additionally, the migrated cells differentiated into mature epithelial cells. Our data, therefore, suggest that local delivery of high 1,25(OH)2D concentrations is a promising strategy to augment intestinal epithelial repair in IBD patients.

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Qingchang Wenzhong Decoction Accelerates Intestinal Mucosal Healing Through Modulation of Dysregulated Gut Microbiome, Intestinal Barrier and Immune Responses in Mice

Frontiers in Pharmacology ◽

10.3389/fphar.2021.738152 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhongmei Sun ◽

Junxiang Li ◽

Wenting Wang ◽

Yuyue Liu ◽

Jia Liu ◽

...

Keyword(s):

Stem Cells ◽

Gut Microbiota ◽

Intestinal Inflammation ◽

Intestinal Barrier ◽

Mucosal Healing ◽

Intestinal Stem Cells ◽

Mucosal Inflammation ◽

Protective Effects ◽

Fecal Microbiome ◽

Epithelial Regeneration

Inflammatory bowel disease (IBD), a group of multifactorial and inflammatory infirmities, is closely associated with dysregulation of gut microbiota and host metabolome, but effective treatments are currently limited. Qingchang Wenzhong Decoction (QCWZD) is an effective and classical traditional herbal prescription for the treatment of IBD and has been proved to attenuate intestinal inflammation in a model of acute colitis. However, the role of QCWZD in recovery phase of colitis is unclear. Here, we demonstrated that mice treated with QCWZD showed a faster recovery from dextran sulfate sodium (DSS)-induced epithelial injury, accompanied by reduced mucosal inflammation and attenuated intestinal dysbiosis using bacterial 16S rRNA amplicon sequencing compared to those receiving sterile water. The protective effects of QCWZD are gut microbiota dependent, as demonstrated by fecal microbiome transplantation and antibiotics treatment. Gut microbes transferred from QCWZD-treated mice displayed a similar role in mucosal protection and epithelial regeneration as QCWZD on colitis in mice, and depletion of the gut microbiota through antibiotics treatments diminished the beneficial effects of QCWZD on colitis mice. Moreover, metabolomic analysis revealed metabolic profiles alternations in response to the gut microbiota reprogrammed by QCWZD intervention, especially enhanced tryptophan metabolism, which may further accelerate intestinal stem cells-mediated epithelial regeneration to protect the integrity of intestinal mucosa through activation of Wnt/β-catenin signals. Collectively, our results suggested that orally administrated QCWZD accelerates intestinal mucosal healing through the modulation of dysregulated gut microbiota and metabolism, thus regulating intestinal stem cells-mediated epithelial proliferation, and hold promise for novel microbial-based therapies in the treatment of IBD.

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Effect of IL-22 on intestinal stem cells, GVHD-related tissue damage, and GVL.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.6539 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 6539-6539

Author(s):

Alan M. Hanash ◽

Marcel R. M. Van Den Brink ◽

Guoqiang Hua ◽

Richard Kolesnick ◽

Bruce R. Blazar

Keyword(s):

Stem Cells ◽

T Cells ◽

T Cell ◽

Allogeneic Bone Marrow Transplantation ◽

Lymphoid Cells ◽

Receptor Expression ◽

Intestinal Stem Cells ◽

Allogeneic Bone ◽

Epithelial Regeneration ◽

Donor T Cells

6539 Background: Intestinal graft vs. host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (allo-BMT). Strategies to limit GVHD by selective promotion of epithelial regeneration in the absence of immunosuppression are largely unknown. Methods: We investigated the role of IL-22 in allo-BMT by utilizing wild type and IL-22 knockout (KO) mice as donors or recipients in allo-BMT. Results: We found that administration of an anti-IL-22 neutralizing antibody to allo-BMT recipients during the first month post-BMT led to increased GVHD mortality, indicating that IL-22 functioned to reduce GVHD severity post-BMT. In contrast, use of IL-22 KO donor T cells did not impair their ability to eliminate A20 lymphoma cells upon tumor challenge, thus indicating that IL-22 was not essential for donor T cells to mediate graft vs. lymphoma (GVL) responses. BMT with WT donors and recipients indicated that IL-22 levels in small and large intestine were increased after BMT and after radiation injury (RI) without BMT. IL-22 upregulation after RI was dependent on the presence of IL-23p40. Although intestinal IL-22 levels were increased after T cell-depleted (TCD) BMT, intestinal IL-22 was reduced by GVHD, as IL-22 production was mediated by host-derived innate lymphoid cells (ILC) that were eliminated by GVHD. Furthermore, host-derived IL-22 was critical for reduction of GVHD morbidity, mortality, and intestinal pathology. GVHD in IL-22 KO mice led to increased apoptosis in epithelial crypts where the intestinal epithelial stem/progenitor cell niche is located. Immunohistochemistry and immunofluorescence demonstrated IL-22 receptor expression on intestinal stem cells (ISC) and progenitors. Allo-BMT in Lgr5-LacZ reporter mice indicated that ISC were targeted by GVHD, and GVHD in IL-22 KO mice led to dramatic ISC depletion. Conclusions: IL-22 is critical for protection of host epithelium during GVHD and critical for protection of ISC, and it does not contribute to donor T cell GVL responses. These findings may have broad relevance for protection of ISC and intestinal epithelium in clinical GVHD and other inflammatory intestinal diseases, and may be useful for clinical separation of pathologic GVH and therapeutic GVL responses.

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Correction to: The Role of Intestinal Stem Cells in Epithelial Regeneration Following Radiation-Induced Gut Injury

Current Stem Cell Reports ◽

10.1007/s40778-018-0121-0 ◽

2018 ◽

Vol 4 (1) ◽

pp. 95-95

Author(s):

Chang-Kyung Kim ◽

Vincent W. Yang ◽

Agnieszka B. Bialkowska

Keyword(s):

Stem Cells ◽

Intestinal Stem Cells ◽

Epithelial Regeneration ◽

Radiation Induced

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Plasticity of Intestinal Epithelium: Stem Cell Niches and Regulatory Signals

International Journal of Molecular Sciences ◽

10.3390/ijms22010357 ◽

2020 ◽

Vol 22 (1) ◽

pp. 357

Author(s):

Ken Kurokawa ◽

Yoku Hayakawa ◽

Kazuhiko Koike

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Inflammatory Cytokines ◽

Intestinal Epithelium ◽

Intestinal Stem Cells ◽

Signal Pathways ◽

Epithelial Regeneration ◽

Cell Functions ◽

Differentiated Cells ◽

Stem Cell Niches

The discovery of Lgr5+ intestinal stem cells (ISCs) triggered a breakthrough in the field of ISC research. Lgr5+ ISCs maintain the homeostasis of the intestinal epithelium in the steady state, while these cells are susceptible to epithelial damage induced by chemicals, pathogens, or irradiation. During the regeneration process of the intestinal epithelium, more quiescent +4 stem cells and short-lived transit-amplifying (TA) progenitor cells residing above Lgr5+ ISCs undergo dedifferentiation and act as stem-like cells. In addition, several recent reports have shown that a subset of terminally differentiated cells, including Paneth cells, tuft cells, or enteroendocrine cells, may also have some degree of plasticity in specific situations. The function of ISCs is maintained by the neighboring stem cell niches, which strictly regulate the key signal pathways in ISCs. In addition, various inflammatory cytokines play critical roles in intestinal regeneration and stem cell functions following epithelial injury. Here, we summarize the current understanding of ISCs and their niches, review recent findings regarding cellular plasticity and its regulatory mechanism, and discuss how inflammatory cytokines contribute to epithelial regeneration.

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Bile Acids Signal via TGR5 to Activate Intestinal Stem Cells and Epithelial Regeneration

Gastroenterology ◽

10.1053/j.gastro.2020.05.067 ◽

2020 ◽

Vol 159 (3) ◽

pp. 956-968.e8 ◽

Cited By ~ 3

Author(s):

Giovanni Sorrentino ◽

Alessia Perino ◽

Ece Yildiz ◽

Gaby El Alam ◽

Maroun Bou Sleiman ◽

...

Keyword(s):

Stem Cells ◽

Bile Acids ◽

Intestinal Stem Cells ◽

Epithelial Regeneration

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Bach2 Deficiency Promotes Intestinal Epithelial Regeneration by Accelerating DNA Repair in Intestinal Stem Cells

Stem Cell Reports ◽

10.1016/j.stemcr.2020.12.005 ◽

2020 ◽

Author(s):

Yuanchuang Li ◽

Xinxin Rao ◽

Peiyuan Tang ◽

Shengzhi Chen ◽

Qiang Guo ◽

...

Keyword(s):

Stem Cells ◽

Dna Repair ◽

Intestinal Stem Cells ◽

Intestinal Epithelial ◽

Epithelial Regeneration

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Re-entry into mitosis and regeneration of intestinal stem cells through enteroblast dedifferentiation in Drosophila midguts

10.1101/2021.11.22.469515 ◽

2021 ◽

Author(s):

Aiguo Tian ◽

Virginia Morejon ◽

Sarah Kohoutek ◽

Yi-Chun Huang ◽

Wu-Min Deng ◽

...

Keyword(s):

Stem Cells ◽

Pathogenic Bacteria ◽

Growth Factor Receptor ◽

Lineage Tracing ◽

Intestinal Stem Cells ◽

Stem Cell Marker ◽

Secretory Cells ◽

Ras Signaling ◽

Epithelial Regeneration ◽

Resident Stem Cells

Many adult tissues and organs including the intestine rely on resident stem cells to maintain homeostasis. In mammalian intestines, upon ablation of resident stem cells, the progenies of intestinal stem cells (ISCs) such as secretory cells and tuft cells can dedifferentiate to generate ISCs to drive epithelial regeneration, but whether and how the ISC progenies dedifferentiate to generate ISCs under physiological conditions remains unknown. Here we show that infection of pathogenic bacteria induces enteroblasts (EBs) as one type of ISC progenies to re-enter the mitotic cycle in the Drosophila intestine. The re-entry into mitosis is dependent on epithermal growth factor receptor (EGFR)-Ras signaling and ectopic activation of EGFR-Ras signaling in EBs is sufficient to drive EBs cell-autonomously to re-enter into mitosis. In addition, we examined whether EBs gain ISC identity as a prerequisite to divide, but the immunostaining with stem cell marker Delta shows that these dividing EBs do not gain ISC identity. After employing lineage tracing experiments, we further demonstrate that EBs dedifferentiate to generate functional ISCs after symmetric divisions of EBs. Together, our study in Drosophila intestines uncovers a new role of EGFR-Ras signaling in regulating re-entry into mitosis and dedifferentiation during regeneration and reveals a novel mechanism by which ISC progenies undergo dedifferentiation through a mitotic division, which has important implication to mammalian tissue homeostasis and tumorigenesis.

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Cathelicidin-WA Protects Against LPS-Induced Gut Damage Through Enhancing Survival and Function of Intestinal Stem Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.685363 ◽

2021 ◽

Vol 9 ◽

Author(s):

Sisi Wang ◽

Lixia Kai ◽

Luoyi Zhu ◽

Bocheng Xu ◽

Nana Chen ◽

...

Keyword(s):

Stem Cells ◽

Critical Role ◽

Intestinal Barrier ◽

Intestinal Stem Cells ◽

Intestinal Barrier Function ◽

Intestinal Damage ◽

Epithelial Regeneration ◽

Gut Damage ◽

And Function ◽

Lps Treatment

Preservation of intestinal stem cells (ISCs) plays a critical role in initiating epithelial regeneration after intestinal injury. Cathelicidin peptides have been shown to participate in regulating intestinal damage repair. However, it is not known how exactly Cathelicidin-WA (CWA) exert its function after tissue damage. Using a gut injury model in mice involving Lipopolysaccharide (LPS), we observed that CWA administration significantly improved intestinal barrier function, preserved ISCs survival, and augmented ISCs viability within the small intestine (SI) under LPS treatment. In addition, CWA administration effectively prevented proliferation stops and promoted the growth of isolated crypts. Mechanistically, our results show that the appearance of γH2AX was accompanied by weakened expression of SETDB1, a gene that has been reported to safeguard genome stability. Notably, we found that CWA significantly rescued the decreased expression of SETDB1 and reduced DNA damage after LPS treatment. Taken together, CWA could protect against LPS-induced gut damage through enhancing ISCs survival and function. Our results suggest that CWA may become an effective therapeutic regulator to treat intestinal diseases and infections.

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