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1
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Liang G, Ma Y, Deng P, Li S, He C, He H, Liu H, Fan Y, Li Z. Role of cell-based therapies in digestive disorders: Obstacles and opportunities. Regen Ther 2025; 29:1-18. [PMID: 40124469 PMCID: PMC11925584 DOI: 10.1016/j.reth.2025.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 02/01/2025] [Accepted: 02/20/2025] [Indexed: 03/25/2025] Open
Abstract
Stem cell-based therapies have emerged as a promising frontier in the treatment of gastrointestinal disorders, offering potential solutions for challenges posed by conventional treatments. This review comprehensively examines recent advancements in cell-based therapeutic strategies, particularly focusing on stem cell applications, immunotherapy, and cellular therapies for digestive diseases. It highlights the successful differentiation of enteric neural progenitors from pluripotent stem cells and their application in animal models, such as Hirschsprung disease. Furthermore, the review evaluates clinical trials and experimental studies demonstrating the potential of stem cells in regenerating damaged tissues, modulating immune responses, and promoting healing in conditions like Crohn's disease and liver failure. By addressing challenges, such as scalability, immunogenicity, and ethical considerations, the review underscores the translational opportunities and obstacles in realizing the clinical potential of these therapies. Concluding with an emphasis on future directions, the study provides insights into optimizing therapeutic efficacy and fostering innovations in personalized medicine for digestive disorders.
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Affiliation(s)
- Guodong Liang
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
| | - Yuehan Ma
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
| | - Ping Deng
- Medical Department, Jilin Cancer Hospital, Changchun 130012, China
| | - Shufeng Li
- First Department of Gynecological Tumor, Jilin Cancer Hospital, Changchun 130012, China
| | - Chunyan He
- Department of Anaesthesia, Jilin Cancer Hospital, Changchun 130012, China
| | - Haihang He
- Department of Otorhinolaryngology, Oral Maxillofacial, Head and Neck, Jilin Cancer Hospital, Changchun 130012, China
| | - Hairui Liu
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
| | - Yunda Fan
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
| | - Ze Li
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
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2
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Tonini L, Ahn C. Latest Advanced Techniques for Improving Intestinal Organoids Limitations. Stem Cell Rev Rep 2025:10.1007/s12015-025-10894-9. [PMID: 40388043 DOI: 10.1007/s12015-025-10894-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/06/2025] [Indexed: 05/20/2025]
Abstract
Intestinal organoids are valuable tools across different disciplines, from a clinical aspect to the biomedical research, providing a unique perspective on the complexity of the gastrointestinal system. They are alternatives to common cell lines as they can offer insights into architectural functionality and reduce the use of animal models. A deeper understanding of their organoid characteristics is required to harness their full potential. Despite their beneficial uses and multiple advantages, organoids have limitations that remain unaddressed. This review aims to elucidate the principal limitations of intestinal organoids, investigate structural defects such as the deficiency in a vascularized and lymphatic system, and absence of the microbiome, restrictions in mimicking the physiological gut model, including the lack of an acid-neutralizing system or a shortage of digestive enzymes, and the difficulties in their long-term maintenance and polarity accessibility. Development of innovative techniques to address these limitations will lead to improve in vivo recapitulation and pioneering further advancements in this field.
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Affiliation(s)
- Lisa Tonini
- Laboratory of Veterinary Physiology, College of Veterinary Medicine, Jeju National University, Jeju, 63243, Republic of Korea
| | - Changhwan Ahn
- Laboratory of Veterinary Physiology, College of Veterinary Medicine, Jeju National University, Jeju, 63243, Republic of Korea.
- Veterinary Medical Research Institute, Jeju National University, Jeju, 63243, Republic of Korea.
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3
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Keister BD, Mesa KR, Blagoev KB. Apoptotic cells may drive cell death in hair follicles during their regression cycle. Oncotarget 2023; 14:893-899. [PMID: 37861373 PMCID: PMC10588663 DOI: 10.18632/oncotarget.28529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 09/21/2023] [Indexed: 10/21/2023] Open
Abstract
Intravital microscopy in live mice has shown that the elimination of epithelial cells during hair follicle regression involves supra-basal cell differentiation and basal cell apoptosis through synergistic action of TGF-β (transforming growth factor) and mesenchymal-epithelial interactions. In this process the basal epithelial cells are not internally committed to death and the mesenchymal dermal papilla (DP) plays essential role in death induction. Because the DP cells are not necessary for completion of the cycle but only for its initiation it is still an open question what is the mechanism leading to the propagation of apoptosis towards the regenerative stem cell population. Here, we use a quantitative analysis of the length of hair follicles during their regression cycle. The data are consistent with a propagation mechanism driven by apoptotic cells inducing apoptosis in their neighboring cells. The observation that the apoptosis slows down as the apoptotic front approaches the stem cells at the end of the follicle is consistent with a gradient of a pro-survival signal sent by these stem cells. An experiment that can falsify this mechanism is proposed.
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Affiliation(s)
- Bradley D. Keister
- National Science Foundation, Physics Division, Alexandria, VA 22230, USA
| | - Kailin R. Mesa
- The Jane Coffin Childs Memorial Fund for Medical Research, New Haven, CT 06520, USA
- Department of Genetics and Dermatology, Yale Stem Cell Center, Yale Cancer Center, Yale School of Medicine, New Haven, CT 06510, USA
| | - Krastan B. Blagoev
- National Science Foundation, Physics Division, Alexandria, VA 22230, USA
- Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218, USA
- Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia 1113, Bulgaria
- Institut Curie, PSL Research University, Sorbonne Université, CNRS UMR3664, Laboratoire Dynamique du Noyau, Paris 75005, France
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Farrelly O, Suzuki-Horiuchi Y, Brewster M, Kuri P, Huang S, Rice G, Bae H, Xu J, Dentchev T, Lee V, Rompolas P. Two-photon live imaging of single corneal stem cells reveals compartmentalized organization of the limbal niche. Cell Stem Cell 2021; 28:1233-1247.e4. [PMID: 33984283 DOI: 10.1016/j.stem.2021.02.022] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 11/18/2020] [Accepted: 02/16/2021] [Indexed: 12/11/2022]
Abstract
The functional heterogeneity of resident stem cells that support adult organs is incompletely understood. Here, we directly visualize the corneal limbus in the eyes of live mice and identify discrete stem cell niche compartments. By recording the life cycle of individual stem cells and their progeny, we directly analyze their fates and show that their location within the tissue can predict their differentiation status. Stem cells in the inner limbus undergo mostly symmetric divisions and are required to sustain the population of transient progenitors that support corneal homeostasis. Using in situ photolabeling, we captured their progeny exiting the niche before moving centripetally in unison. The long-implicated slow-cycling stem cells are functionally distinct and display local clonal dynamics during homeostasis but can contribute to corneal regeneration after injury. This study demonstrates how the compartmentalized organization of functionally diverse stem cell populations supports the maintenance and regeneration of an adult organ.
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Affiliation(s)
- Olivia Farrelly
- Department of Dermatology, Department of Cell and Developmental Biology, Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Yoko Suzuki-Horiuchi
- Department of Dermatology, Department of Cell and Developmental Biology, Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Megan Brewster
- Department of Dermatology, Department of Cell and Developmental Biology, Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Paola Kuri
- Department of Dermatology, Department of Cell and Developmental Biology, Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Sixia Huang
- Department of Dermatology, Department of Cell and Developmental Biology, Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Gabriella Rice
- Department of Dermatology, Department of Cell and Developmental Biology, Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Hyunjin Bae
- Department of Dermatology, Department of Cell and Developmental Biology, Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Jianming Xu
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Tzvete Dentchev
- Department of Dermatology, Department of Cell and Developmental Biology, Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Vivian Lee
- Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Panteleimon Rompolas
- Department of Dermatology, Department of Cell and Developmental Biology, Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
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5
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Wan J, Dai H, Zhang X, Liu S, Lin Y, Somani AK, Xie J, Han J. Distinct transcriptomic landscapes of cutaneous basal cell carcinomas and squamous cell carcinomas. Genes Dis 2021; 8:181-192. [PMID: 33997165 PMCID: PMC8099692 DOI: 10.1016/j.gendis.2019.10.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 10/06/2019] [Accepted: 10/08/2019] [Indexed: 12/17/2022] Open
Abstract
The majority of non-melanoma skin cancer (NMSC) is cutaneous basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), which are also called keratinocyte carcinomas, as both of them originate from keratinocytes. The incidence of keratinocyte carcinomas is over 5 million per year in the US, three-fold higher than the total incidence of all other types of cancer combined. While there are several reports on gene expression profiling of BCC and SCC, there are significant variations in the reported gene expression changes in different studies. One reason is that tumor-adjacent normal skin specimens were not included in many studies as matched controls. Furthermore, while numerous studies of skin stem cells in mouse models have been reported, their relevance to human skin cancer remains unknown. In this report, we analyzed gene expression profiles of paired specimens of keratinocyte carcinomas with their matched normal skin tissues as the control. Among several novel findings, we discovered a significant number of zinc finger encoding genes up-regulated in human BCC. In BCC, a novel link was found between hedgehog signaling, Wnt signaling, and the cilium. While the SCC cancer-stem-cell gene signature is shared between human and mouse SCCs, the hair follicle stem-cell signature of mice was not highly represented in human SCC. Differential gene expression (DEG) in human BCC shares gene signature with both bulge and epidermal stem cells. We have also determined that human BCCs and SCCs have distinct gene expression patterns, and some of them are not fully reflected in current mouse models.
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Affiliation(s)
- Jun Wan
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- School of Informatics and Computing, Indiana University – Purdue University at Indianapolis, Indianapolis, IN, 46202, USA
| | - Hongji Dai
- Department of Epidemiology and Biostatistics, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300000, PR China
| | - Xiaoli Zhang
- Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Sheng Liu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Yuan Lin
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, 46202, USA
| | - Ally-Khan Somani
- Dermatologic Surgery & Cutaneous Oncology Division, Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Jingwu Xie
- Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Jiali Han
- Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, 46202, USA
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6
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Dosh RH, Jordan-Mahy N, Sammon C, Le Maitre CL. Use of l-pNIPAM hydrogel as a 3D-scaffold for intestinal crypts and stem cell tissue engineering. Biomater Sci 2020; 7:4310-4324. [PMID: 31410428 DOI: 10.1039/c9bm00541b] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Intestinal stem cells hold great potential in tissue regeneration of the intestine, however, there are key limitations in their culture in vitro. We previously reported a novel synthetic non-biodegradable hydrogel as a 3D culture model for intestinal epithelium using Caco2 and HT29-MTX cells. Here, we investigated the potential of this system as a 3D scaffold for crypts and single intestinal stem cells to support long-term culture and differentiation. Intestinal crypts were extracted from murine small intestines and Lgr5+ stem cells isolated by magnetic activated cell sorting. Crypts and stem cells were suspended within Matrigel or l-pNIPAM for 14 days or suspended within Matrigel for 7 days then released, dissociated, and suspended within, or on l-pNIPAM hydrogel for 28 days. Cellular behaviour and phenotype were determined by histology and immunohistochemistry for stem cell and differentiation markers: Lgr5, E-cadherin MUC2 chromograninA and lysozymes. Isolated crypts and Lgr5+ intestinal stem cells formed enteroids with a central lumen surrounded by multiple crypt-like buds when cultured in Matrigel. In contrast, when crypts and stem cells were directly suspended within, or layered on l-pNIPAM hydrogel under dynamic culture conditions they formed spherical balls of cells, with no central lumen. When enteroids were initially formed in Matrigel from crypts or single Lgr5+ intestinal stem cells and dissociated into small fragments or single cells and transferred to l-pNIPAM hydrogel they formed new larger enteroids with numerous crypt-like buds. These crypt-like buds showed the presence of mucin-producing cells, which resembled goblet cells, scattered throughout their structures. Immunohistochemistry staining also showed the expression of Lgr5 and differentiation markers of all the main intestinal cell types including: enterocytes, goblet cells, enteroendocrine and Paneth cells. This demonstrated that l-pNIPAM hydrogel supported long-term culture of crypts and Lgr5+ stem cells and promoted intestinal cell differentiation.
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Affiliation(s)
- Rasha H Dosh
- Biomolecular Sciences Research Centre, Sheffield Hallam University, S1 1WB, UK.
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7
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Abstract
Radiotherapy is used in >50% of patients with cancer, both for curative and palliative purposes. Radiotherapy uses ionizing radiation to target and kill tumour tissue, but normal tissue can also be damaged, leading to toxicity. Modern and precise radiotherapy techniques, such as intensity-modulated radiotherapy, may prevent toxicity, but some patients still experience adverse effects. The physiopathology of toxicity is dependent on many parameters, such as the location of irradiation or the functional status of organs at risk. Knowledge of the mechanisms leads to a more rational approach for controlling radiotherapy toxicity, which may result in improved symptom control and quality of life for patients. This improved quality of life is particularly important in paediatric patients, who may live for many years with the long-term effects of radiotherapy. Notably, signs and symptoms occurring after radiotherapy may not be due to the treatment but to an exacerbation of existing conditions or to the development of new diseases. Although differential diagnosis may be difficult, it has important consequences for patients.
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8
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Lim SL, Damnernsawad A, Shyamsunder P, Chng WJ, Han BC, Xu L, Pan J, Pravin DP, Alkan S, Tyner JW, Koeffler HP. Proteolysis targeting chimeric molecules as therapy for multiple myeloma: efficacy, biomarker and drug combinations. Haematologica 2019; 104:1209-1220. [PMID: 30606790 PMCID: PMC6545861 DOI: 10.3324/haematol.2018.201483] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 01/02/2019] [Indexed: 12/31/2022] Open
Abstract
Proteolysis targeting chimeric molecule ARV 825 causes ubiquitination of bromodomains resulting in their efficient degradation by proteasome activity. Bromodomain degradation down-regulates MYC transcription contributing to growth inhibition of various human cancers. We examined the therapeutic potential of ARV 825 against multiple myeloma (MM) cells both in vitro and in vivo In a dose-dependent manner, ARV 825 inhibited proliferation of 13 human MM cell lines and three fresh patient samples, and was associated with cell cycle arrest and apoptosis. ARV 825 rapidly and efficiently degraded BRD 2 and BRD 4. Sensitivity of MM cells to ARV 825 was positively correlated with cereblon levels. RNA sequencing analysis showed important genes such as CCR1, RGS, MYB and MYC were down-regulated by ARV 825. A total of 170 small molecule inhibitors were screened for synergy with ARV 825. Combination of ARV 825 with inhibitor of either dual PI3K/mTOR, CRM1, VEGFR, PDGFRα/b, FLT3, IGF-1R, protein kinase C, CBP-EP300 or JAK1/2 showed synergistic activity. Importantly, ARV 825 significantly inhibited the growth of MM xenografts and improved mice survival. Taken together, our results, in conjunction with recently published findings, provide a rationale for investigating the efficacy of ARV 825 for MM, use of cereblon as a biomarker for therapy of MM patients, and the combination of ARV 825 with small molecule inhibitors to improve the outcome of MM patients.
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Affiliation(s)
- Su Lin Lim
- Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Alisa Damnernsawad
- Division of Hematology and Medical Oncology, Oregon Health and Science University Knight Cancer Institute, Portland, OR, USA
| | - Pavithra Shyamsunder
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Wee Joo Chng
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | | | - Liang Xu
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Jian Pan
- Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Dakle Pushkar Pravin
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Serhan Alkan
- Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Jeffrey W Tyner
- Division of Hematology and Medical Oncology, Oregon Health and Science University Knight Cancer Institute, Portland, OR, USA
| | - H Phillip Koeffler
- Cedars Sinai Medical Center, Los Angeles, CA, USA.,Cancer Science Institute of Singapore, National University of Singapore, Singapore
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9
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Brain Organoids: Expanding Our Understanding of Human Development and Disease. Results Probl Cell Differ 2018; 66:183-206. [PMID: 30209660 DOI: 10.1007/978-3-319-93485-3_8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Stem cell-derived brain organoids replicate important stages of the prenatal human brain development and combined with the induced pluripotent stem cell (iPSC) technology offer an unprecedented model for investigating human neurological diseases including autism and microcephaly. We describe the history and birth of organoids and their application, focusing on cerebral organoids derived from embryonic stem cells and iPSCs. We discuss new insights into organoid-based model of schizophrenia and shed light on challenges and future applications of organoid-based disease model system. This review also suggests hitherto unrevealed potential applications of organoids in combining with new technologies such as nanophotonics/optogenomics for controlling brain development and atomic force microscopy for studying mechanical forces that shape the developing brain.
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10
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Petersen N, Reimann F, Bartfeld S, Farin HF, Ringnalda FC, Vries RGJ, van den Brink S, Clevers H, Gribble FM, de Koning EJP. Generation of L cells in mouse and human small intestine organoids. Diabetes 2014; 63:410-20. [PMID: 24130334 PMCID: PMC4306716 DOI: 10.2337/db13-0991] [Citation(s) in RCA: 100] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Upon a nutrient challenge, L cells produce glucagon-like peptide 1 (GLP-1), a powerful stimulant of insulin release. Strategies to augment endogenous GLP-1 production include promoting L-cell differentiation and increasing L-cell number. Here we present a novel in vitro platform to generate functional L cells from three-dimensional cultures of mouse and human intestinal crypts. We show that short-chain fatty acids selectively increase the number of L cells, resulting in an elevation of GLP-1 release. This is accompanied by the upregulation of transcription factors associated with the endocrine lineage of intestinal stem cell development. Thus, our platform allows us to study and modulate the development of L cells in mouse and human crypts as a potential basis for novel therapeutic strategies in patients with type 2 diabetes.
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Affiliation(s)
- Natalia Petersen
- Hubrecht Institute for Development Biology and Stem Cell Research, Utrecht, Netherlands
| | - Frank Reimann
- Cambridge Institute for Medical Research, Department of Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, UK
| | - Sina Bartfeld
- Hubrecht Institute for Development Biology and Stem Cell Research, Utrecht, Netherlands
| | - Henner F. Farin
- Hubrecht Institute for Development Biology and Stem Cell Research, Utrecht, Netherlands
| | - Femke C. Ringnalda
- Hubrecht Institute for Development Biology and Stem Cell Research, Utrecht, Netherlands
| | - Robert G. J. Vries
- Hubrecht Institute for Development Biology and Stem Cell Research, Utrecht, Netherlands
| | | | - Hans Clevers
- Hubrecht Institute for Development Biology and Stem Cell Research, Utrecht, Netherlands
- Utrecht University Medical Center, Utrecht, Netherlands
| | - Fiona M. Gribble
- Cambridge Institute for Medical Research, Department of Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge, UK
| | - Eelco J. P. de Koning
- Hubrecht Institute for Development Biology and Stem Cell Research, Utrecht, Netherlands
- Department of Nephrology, Leiden University Medical Center, Leiden, Netherlands
- Department of Endocrinology, Leiden University Medical Center, Leiden, Netherlands
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11
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Colletti E, El Shabrawy D, Soland M, Yamagami T, Mokhtari S, Osborne C, Schlauch K, Zanjani ED, Porada CD, Almeida-Porada G. EphB2 isolates a human marrow stromal cell subpopulation with enhanced ability to contribute to the resident intestinal cellular pool. FASEB J 2013; 27:2111-21. [PMID: 23413357 DOI: 10.1096/fj.12-205054] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
To identify human bone marrow stromal cell (BMSC) subsets with enhanced ability to engraft/contribute to the resident intestinal cellular pool, we transplanted clonally derived BMSCs into fetal sheep. Analysis at 75 d post-transplantation showed 2 of the 6 clones engrafting the intestine at 4- to 5-fold higher levels (5.03±0.089 and 5.04±0.15%, respectively) than the other clones (P<0.01), correlating with the percentage of donor-derived Musashi-1(+) (12.01-14.17 vs. 1.2-3.8%; P<0.01) or leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5)(+) cells within the intestinal stem cell (ISC) region. Phenotypic and transcriptome analysis determined that the clones with enhanced intestinal contribution expressed high levels of Ephrin type B receptor 2 (EphB2). Intestinal explants demonstrated proliferation of the engrafted cells and ability to generate crypt-like structures in vitro still expressing EphB2. Additional transplants based on BMSC EphB2 expression demonstrated that, at 7 d post-transplant, the EphB2(high) BMSCs engrafted in the ISC region at levels of 2.1 ± 0.2%, while control EphB2(low) BMSCs engrafted at 0.3 ± 0.1% (P<0.01). Therefore we identified a marker for isolating and culturing an expandable subpopulation of BMSCs with enhanced intestinal homing and contribution to the ISC region.
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Affiliation(s)
- Evan Colletti
- Department of Animal Biotechnology, University of Nevada, Reno, Nevada, USA
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12
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Burra P, Bizzaro D, Ciccocioppo R, Marra F, Piscaglia AC, Porretti L, Gasbarrini A, Russo FP. Therapeutic application of stem cells in gastroenterology: an up-date. World J Gastroenterol 2011; 17:3870-3880. [PMID: 22025875 PMCID: PMC3198016 DOI: 10.3748/wjg.v17.i34.3870] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2010] [Revised: 03/07/2011] [Accepted: 03/14/2011] [Indexed: 02/06/2023] Open
Abstract
Adult stem cells represent the self-renewing progenitors of numerous body tissues, and they are currently classified according to their origin and differentiation ability. In recent years, the research on stem cells has expanded enormously and holds therapeutic promises for many patients suffering from currently disabling diseases. This paper focuses on the possible use of stem cells in the two main clinical settings in gastroenterology, i.e., hepatic and intestinal diseases, which have a strong impact on public health worldwide. Despite encouraging results obtained in both regenerative medicine and immune-mediated conditions, further studies are needed to fully understand the biology of stem cells and carefully assess their putative oncogenic properties. Moreover, the research on stem cells arouses fervent ethical, social and political debate. The Italian Society of Gastroenterology sponsored a workshop on stem cells held in Verona during the XVI Congress of the Federation of Italian Societies of Digestive Diseases (March 6-9, 2010). Here, we report on the issues discussed, including liver and intestinal diseases that may benefit from stem cell therapy, the biology of hepatic and intestinal tissue repair, and stem cell usage in clinical trials.
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13
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Reizel Y, Chapal-Ilani N, Adar R, Itzkovitz S, Elbaz J, Maruvka YE, Segev E, Shlush LI, Dekel N, Shapiro E. Colon stem cell and crypt dynamics exposed by cell lineage reconstruction. PLoS Genet 2011; 7:e1002192. [PMID: 21829376 PMCID: PMC3145618 DOI: 10.1371/journal.pgen.1002192] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2011] [Accepted: 06/05/2011] [Indexed: 12/22/2022] Open
Abstract
Stem cell dynamics in vivo are often being studied by lineage tracing methods. Our laboratory has previously developed a retrospective method for reconstructing cell lineage trees from somatic mutations accumulated in microsatellites. This method was applied here to explore different aspects of stem cell dynamics in the mouse colon without the use of stem cell markers. We first demonstrated the reliability of our method for the study of stem cells by confirming previously established facts, and then we addressed open questions. Our findings confirmed that colon crypts are monoclonal and that, throughout adulthood, the process of monoclonal conversion plays a major role in the maintenance of crypts. The absence of immortal strand mechanism in crypts stem cells was validated by the age-dependent accumulation of microsatellite mutations. In addition, we confirmed the positive correlation between physical and lineage proximity of crypts, by showing that the colon is separated into small domains that share a common ancestor. We gained new data demonstrating that colon epithelium is clustered separately from hematopoietic and other cell types, indicating that the colon is constituted of few progenitors and ruling out significant renewal of colonic epithelium from hematopoietic cells during adulthood. Overall, our study demonstrates the reliability of cell lineage reconstruction for the study of stem cell dynamics, and it further addresses open questions in colon stem cells. In addition, this method can be applied to study stem cell dynamics in other systems. The study of stem cell and tissue dynamics in vivo is often carried out by lineage tracing methods that depend on the presence of specific markers and on the availability of stem cells. In the current study, we applied a novel method for the reconstruction of cell lineage trees from microsatellite mutations accumulated during mouse life. We focused on the intestinal epithelium, since its stem cells were intensively studied by various tracing methods that clarified many aspects of their dynamics. We first showed the reliability of our method by confirming three previously established facts: the existence of “monoclonal conversion,” the absence of an immortal strand mechanism in colon stem cells, and the separation of the colon into small domains each with a common ancestor. We also answered a few open questions, showing that the colon's lineage is separated from other lineages such as the hematopoietic and pancreatic lineages. Overall, our work presents a new approach for the study of stem cell dynamics and can similarly be used for studying stem cell dynamics in other systems.
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Affiliation(s)
- Yitzhak Reizel
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Noa Chapal-Ilani
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel
| | - Rivka Adar
- Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel
| | - Shalev Itzkovitz
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel
- Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel
| | - Judith Elbaz
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Yosef E. Maruvka
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel
| | - Elad Segev
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel
- Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel
| | - Liran I. Shlush
- Rappaport Faculty of Medicine and Research Institute, Technion and Rambam Medical Center, Haifa, Israel
| | - Nava Dekel
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Ehud Shapiro
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel
- Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel
- * E-mail:
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Ouellette AJ. Paneth cell α-defensins in enteric innate immunity. Cell Mol Life Sci 2011; 68:2215-29. [PMID: 21560070 PMCID: PMC4073591 DOI: 10.1007/s00018-011-0714-6] [Citation(s) in RCA: 105] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2011] [Revised: 04/26/2011] [Accepted: 04/26/2011] [Indexed: 12/18/2022]
Abstract
Paneth cells at the base of small intestinal crypts of Lieberkühn secrete high levels of α-defensins in response to cholinergic and microbial stimuli. Paneth cell α-defensins are broad spectrum microbicides that function in the extracellular environment of the intestinal lumen, and they are responsible for the majority of secreted bactericidal peptide activity. Paneth cell α-defensins confer immunity to oral infection by Salmonella enterica serovar Typhimurium, and they are major determinants of the composition of the small intestinal microbiome. In addition to host defense molecules such as α-defensins, lysozyme, and Pla2g2a, Paneth cells also produce and release proinflammatory mediators as components of secretory granules. Disruption of Paneth cell homeostasis, with subsequent induction of endoplasmic reticulum stress, autophagy, or apoptosis, contributes to inflammation in diverse genetic and experimental mouse models.
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Affiliation(s)
- André Joseph Ouellette
- Department of Pathology and Laboratory Medicine, Keck School of Medicine of the University of Southern California, USC/Norris Cancer Center, Los Angeles, CA 90089-9601, USA.
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15
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Shaw RL, Kohlmaier A, Polesello C, Veelken C, Edgar BA, Tapon N. The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration. Development 2010; 137:4147-58. [PMID: 21068063 DOI: 10.1242/dev.052506] [Citation(s) in RCA: 251] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Intestinal stem cells (ISCs) in the adult Drosophila midgut proliferate to self-renew and to produce differentiating daughter cells that replace those lost as part of normal gut function. Intestinal stress induces the activation of Upd/Jak/Stat signalling, which promotes intestinal regeneration by inducing rapid stem cell proliferation. We have investigated the role of the Hippo (Hpo) pathway in the Drosophila intestine (midgut). Hpo pathway inactivation in either the ISCs or the differentiated enterocytes induces a phenotype similar to that observed under stress situations, including increased stem cell proliferation and expression of Jak/Stat pathway ligands. Hpo pathway targets are induced by stresses such as bacterial infection, suggesting that the Hpo pathway functions as a sensor of cellular stress in the differentiated cells of the midgut. In addition, Yki, the pro-growth transcription factor target of the Hpo pathway, is required in ISCs to drive the proliferative response to stress. Our results suggest that the Hpo pathway is a mediator of the regenerative response in the Drosophila midgut.
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Affiliation(s)
- Rachael L Shaw
- Apoptosis and Proliferation Control Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3LY, UK
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16
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Abstract
PURPOSE OF REVIEW Recent evidence shows that disruption of Paneth cell homeostasis by induction of endoplasmic reticulum stress or autophagy, with consequent apoptosis, contributes to inflammation and morbidity in a variety of experimental mouse models. RECENT FINDINGS Recent advances show that proinflammatory mediators in Paneth cell dense core secretory granules mediate tumor necrosis factor-α-induced shock, that Paneth cell α-defensins modulate the composition of the small intestinal microflora, that development of crypt organoid culture systems provides a novel means for investigating the crypt microenvironment, and that varied genetic defects that disrupt Paneth cell homeostasis are emergent as risk factors in inflammatory bowel disease. SUMMARY This recent literature identifies Paneth cells as particularly sensitive targets of endoplasmic reticulum stress responses and implicates this unique small intestinal lineage in inflammatory bowel disease pathogenesis resulting from diverse heritable and environmental causes.
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Affiliation(s)
- André J Ouellette
- Department of Pathology and Laboratory Medicine, Keck School of Medicine of The University of Southern California, Los Angeles, California 90089-9601, USA.
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Greco V, Guo S. Compartmentalized organization: a common and required feature of stem cell niches? Development 2010; 137:1586-94. [PMID: 20430743 DOI: 10.1242/dev.041103] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
A key question in the stem cell field is how to balance the slow cycling of stem cells with active organ growth. Recent studies of the hair follicle stem cell niche have shown that this can be achieved by organizing the stem cell niche into two compartments: one that engages in immediate, rapid new growth and one that contributes later to long-term growth that fuels hair regeneration. Based on these and other recent findings, we propose that several other adult stem cell niches, including those in the blood, intestine and brain, have a similar bi-compartmental organization and that stem cells might work cooperatively with their progeny to sustain tissue regeneration.
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Affiliation(s)
- Valentina Greco
- Department of Genetics, Yale University School of Medicine and Yale Stem Cell Center, SHM I 141A, New Haven, CT 06510, USA.
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Yamada Y, Watanabe A. Epigenetic Codes in Stem Cells and Cancer Stem Cells. EPIGENETICS AND CANCER, PART A 2010; 70:177-99. [DOI: 10.1016/b978-0-12-380866-0.60007-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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