Apoptotic colopathy: a pragmatic approach to diagnosis

Karamchandani, Dipti M.; Chetty, Runjan

doi:10.1136/jclinpath-2018-205388

Cited by 27 publications

(31 citation statements)

References 34 publications

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“…Remarkably, intestinal pathology due to IEC-specific MCL1 deficiency shared hallmark features with IBD, including barrier dysfunction, chronic inflammation, increased IEC apoptosis, hyperproliferation, and impaired ISC differentiation. 1 , 3 , 5 Thus, Mcl1 ΔIEC mice may represent a pertinent preclinical model of both apoptotic enterocolopathy and IBD, while also opening up the possibility that (even a temporally restricted) dysregulation of MCL1 may contribute to the development of these, and similar, conditions.…”

Section: Discussionmentioning

confidence: 99%

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MCL1 Is Required for Maintenance of Intestinal Homeostasis and Prevention of Carcinogenesis in Mice

et al. 2020

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Background & Aims Intestinal epithelial homeostasis depends on a tightly regulated balance between intestinal epithelial cell (IEC) death and proliferation. While the disruption of several IEC death regulating factors result in intestinal inflammation, the loss of the anti-apoptotic BCL2 family members BCL2 and BCL2L1 has no effect on intestinal homeostasis in mice. We investigated the functions of the antiapoptotic protein MCL1, another member of the BCL2 family, in intestinal homeostasis in mice. Methods We generated mice with IEC-specific disruption of Mcl1 ( Mcl1 ΔIEC mice) or tamoxifen-inducible IEC-specific disruption of Mcl1 (i- Mcl1 ΔIEC mice); these mice and mice with full-length Mcl1 (controls) were raised under normal or germ-free conditions. Mice were analyzed by endoscopy and for intestinal epithelial barrier permeability. Intestinal tissues were analyzed by histology, in situ hybridization, proliferation assays, and immunoblots. Levels of calprotectin, a marker of intestinal inflammation, were measured in intestinal tissues and feces. Results Mcl1 ΔIEC mice spontaneously developed apoptotic enterocolopathy, characterized by increased IEC apoptosis, hyperproliferative crypts, epithelial barrier dysfunction, and chronic inflammation. Loss of MCL1 retained intestinal crypts in a hyperproliferated state and prevented the differentiation of intestinal stem cells. Proliferation of intestinal stem cells in MCL1-deficient mice required WNT signaling and was associated with DNA damage accumulation. By 1 year of age, Mcl1 ΔIEC mice developed intestinal tumors with morphologic and genetic features of human adenomas and carcinomas. Germ-free housing of Mcl1 ΔIEC mice reduced markers of microbiota-induced intestinal inflammation but not tumor development. Conclusion The antiapoptotic protein MCL1, a member of the BCL2 family, is required for maintenance of intestinal homeostasis and prevention of carcinogenesis in mice. Loss of MCL1 results in development of intestinal carcinomas, even under germ-free conditions, and therefore does not involve microbe-induced chronic inflammation. Mcl1 ΔIEC mice might be used to study apoptotic enterocolopathy and inflammatory bowel diseases.

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Section: Discussionmentioning

confidence: 99%

“…IECs display a high cell turnover, necessitating a strictly regulated balance of proliferation and cell death to guarantee intestinal epithelial homeostasis 3 ; however, excessive IEC death is a well-known clinical hallmark of apoptotic enterocolopathy and inflammatory bowel disease (IBD). 3 , 4 , 5 …”

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confidence: 99%

MCL1 Is Required for Maintenance of Intestinal Homeostasis and Prevention of Carcinogenesis in Mice

et al. 2020

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“…However, the use of ApoBDs in disease diagnosis is currently limited to apoptotic colopathy, a histological test of gastrointestinal biopsies. Traditionally, an increase in ApoBD number is indicative of gastrointestinal injury [53]. Nonetheless, this visualisation technique for diagnosis requires high-resolution microscopy, well-trained pathologists and thorough assessments of multiple histological sections [53].…”

Section: Apobds As a Diagnostic Toolmentioning

confidence: 99%

“…Traditionally, an increase in ApoBD number is indicative of gastrointestinal injury [53]. Nonetheless, this visualisation technique for diagnosis requires high-resolution microscopy, well-trained pathologists and thorough assessments of multiple histological sections [53]. A recently developed flow cytometry-based approach [11,54] to quantify ApoBDs may improve the diagnostic accuracy and efficiency in place of the histological examination.…”

Section: Apobds As a Diagnostic Toolmentioning

confidence: 99%

Unleashing the therapeutic potential of apoptotic bodies

Phan

Ozkocak

Poon

2020

Biochemical Society Transactions

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Extracellular vesicles (EVs), membrane-bound vesicles that are naturally released by cells, have emerged as new therapeutic opportunities. EVs, particularly exosomes and microvesicles, can transfer effector molecules and elicit potent responses in recipient cells, making them attractive therapeutic targets and drug delivery platforms. Furthermore, containing predictive biomarkers and often being dysregulated in various disease settings, these EVs are being exploited for diagnostic purposes. In contrast, the therapeutic application of apoptotic bodies (ApoBDs), a distinct type of EVs released by cells undergoing a form of programmed cell death called apoptosis, has been largely unexplored. Recent studies have shed light on ApoBD biogenesis and functions, promisingly implicating their therapeutic potential. In this review, we discuss many strategies to develop ApoBD-based therapies as well as highlight their advantages and challenges, thereby positioning ApoBD for potential EV-based therapy.

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“…41 Viral organisms also cause infectious colitis. Cytomegalovirus can be associated with an increase in apoptosis, 30 helminths. 42 Fungal infections are rare in the Western hemisphere, except in immunosuppressed patients.…”

Section: Infectious Colitismentioning

confidence: 99%

Non-neoplastic colorectal disease biopsies: evaluation and differential diagnosis

2020

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A wide variety of non-neoplastic conditions may be encountered on colorectal biopsy encompassing idiopathic, infectious, vascular and immune-mediated aetiologies. Although interpretation of such biopsies may be challenging, appreciation of the dominant pattern of injury and subsequent host response may allow for a more focused histological diagnosis in the correct clinical and endoscopic setting. This article aims to provide a systematic, methodical approach to the assessment of such biopsies, concentrating mainly on diagnoses other than inflammatory bowel disease.

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Apoptotic colopathy: a pragmatic approach to diagnosis

Cited by 27 publications

References 34 publications

MCL1 Is Required for Maintenance of Intestinal Homeostasis and Prevention of Carcinogenesis in Mice

MCL1 Is Required for Maintenance of Intestinal Homeostasis and Prevention of Carcinogenesis in Mice

Unleashing the therapeutic potential of apoptotic bodies

Non-neoplastic colorectal disease biopsies: evaluation and differential diagnosis

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