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Tian CM, Zhang Y, Yang MF, Xu HM, Zhu MZ, Yao J, Wang LS, Liang YJ, Li DF. Stem Cell Therapy in Inflammatory Bowel Disease: A Review of Achievements and Challenges. J Inflamm Res 2023; 16:2089-2119. [PMID: 37215379 PMCID: PMC10199681 DOI: 10.2147/jir.s400447] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 05/03/2023] [Indexed: 05/24/2023] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory diseases of the gastrointestinal tract. Repeated inflammation can lead to complications, such as intestinal fistula, obstruction, perforation, and bleeding. Unfortunately, achieving durable remission and mucosal healing (MH) with current treatments is difficult. Stem cells (SCs) have the potential to modulate immunity, suppress inflammation, and have anti-apoptotic and pro-angiogenic effects, making them an ideal therapeutic strategy to target chronic inflammation and intestinal damage in IBD. In recent years, hematopoietic stem cells (HSCs) and adult mesenchymal stem cells (MSCs) have shown efficacy in treating IBD. In addition, numerous clinical trials have evaluated the efficiency of MSCs in treating the disease. This review summarizes the current research progress on the safety and efficacy of SC-based therapy for IBD in both preclinical models and clinical trials. We discuss potential mechanisms of SC therapy, including tissue repair, paracrine effects, and the promotion of angiogenesis, immune regulation, and anti-inflammatory effects. We also summarize current SC engineering strategies aimed at enhancing the immunosuppressive and regenerative capabilities of SCs for treating intestinal diseases. Additionally, we highlight current limitations and future perspectives of SC-related therapy for IBD.
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Affiliation(s)
- Cheng-Mei Tian
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
- Department of Emergency, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Yuan Zhang
- Department of Medical Administration, Huizhou Institute of Occupational Diseases Control and Prevention, Huizhou, Guangdong, People’s Republic of China
| | - Mei-Feng Yang
- Department of Hematology, Yantian District People’s Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - Hao-Ming Xu
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China
| | - Min-Zheng Zhu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Li-Sheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Yu-Jie Liang
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - De-Feng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
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Gu G, Lv X, Liu G, Zeng R, Li S, Chen L, Liang Z, Wang H, Lu F, Zhan L, Lv X. Tnfaip6 Secreted by Bone Marrow-Derived Mesenchymal Stem Cells Attenuates TNBS-Induced Colitis by Modulating Follicular Helper T Cells and Follicular Regulatory T Cells Balance in Mice. Front Pharmacol 2021; 12:734040. [PMID: 34707499 PMCID: PMC8542666 DOI: 10.3389/fphar.2021.734040] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/31/2021] [Indexed: 12/16/2022] Open
Abstract
Objective: To investigate the immunological mechanism of bone marrow-derived mesenchymal stem cells (BM-MSCs) in inflammatory bowel disease (IBD). Methods: Mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis were intraperitoneally injected with phosphate-buffered saline, BM-MSCs, BM-MSCs with tumor necrosis factor-induced protein 6 (Tnfaip6) knockdown mediated by RNA interference recombinant adenovirus, and BM-MSCs-infected with control adenovirus or recombinant mouse Tnfaip6. The disease activity index, weight loss, and histological scores were recorded. Serum levels of Tnfaip6 and pro- and anti-inflammatory cytokines, including interleukin (IL)-21, tumor necrosis factor-alpha (TNF-α), IL-10 were measured by enzyme-linked immunosorbent assay. The relative expression levels of these cytokines, B-cell lymphoma 6 (BCL-6) and fork-like transcription factor p3 (Foxp3) in the colon were determined by real-time quantitative PCR (RT-qPCR). BCL-6 and Foxp3 are the master regulators of follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr), respectively. The infiltration of Tfh and Tfr in mesenteric lymph nodes (MLNs) and spleens was analyzed by flow cytometry. Results: Compared to the normal control group, the expression levels of BCL-6 and IL-21 in the colon, Tfh infiltration, and ratios of Tfh/Tfr in the MLNs and spleen, and the serum concentrations of IL-21 and TNF-α increased significantly in the colitis model group (p < 0.05). Intraperitoneal injection of BM-MSCs or Tnfaip6 ameliorated weight loss and clinical and histological severity of colitis, downregulated the expression of BCL-6, IL-21, and TNF-α, upregulated the expression of Foxp3, IL-10, and Tnfaip6 (p < 0.05), increased Tfr and reduced the infiltration of Tfh in the MLNs and spleen, and downregulated the Tfh/Tfr ratio (p < 0.05). On the other hand, BM-MSCs lost the therapeutic effect and immune regulatory functions on Tfh and Tfr after Tnfaip6 knockdown. Conclusion: Tfh increase in the inflamed colon, Tfh decrease and Tfr increase during the colitis remission phase, and the imbalance of the Tfh/Tfr ratio is closely related to the progression of IBD. Tnfaip6 secreted by BM-MSCs alleviates IBD by inhibiting Tfh differentiation, promoting Tfr differentiation, and improving the imbalance of Tfh/Tfr in mice.
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Affiliation(s)
- Guangli Gu
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiaodan Lv
- Department of Clinical Experimental Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Gengfeng Liu
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Ruizhi Zeng
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Shiquan Li
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lan Chen
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhaoliang Liang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Huiqin Wang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Fei Lu
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lingling Zhan
- Department of Clinical Experimental Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiaoping Lv
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Kawai H, Tsujigiwa H, Siar CH, Nakano K, Takabatake K, Fujii M, Hamada M, Tamamura R, Nagatsuka H. Characterization and potential roles of bone marrow-derived stromal cells in cancer development and metastasis. Int J Med Sci 2018; 15:1406-1414. [PMID: 30275769 PMCID: PMC6158661 DOI: 10.7150/ijms.24370] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 04/27/2018] [Indexed: 12/15/2022] Open
Abstract
Background: The tumor microenvironment and its stromal cells play an important role in cancer development and metastasis. Bone marrow-derived cells (BMDCs), a rich source of hematopoietic and mesenchymal stem cells, putatively contribute to this tumoral stroma. However their characteristics and roles within the tumor microenvironment are unclear. In the present study, BMDCs in the tumor microenvironment were traced using the green fluorescent protein (GFP) bone marrow transplantation model. Methods: C57BL/6 mice were irradiated and rescued by bone marrow transplantation from GFP-transgenic mice. Lewis lung cancer cells were inoculated into the mice to generate subcutaneous allograft tumors or lung metastases. Confocal microscopy, immunohistochemistry for GFP, α-SMA, CD11b, CD31, CD34 and CD105, and double-fluorescent immunohistochemistry for GFP-CD11b, GFP-CD105 and GFP-CD31 were performed. Results: Round and dendritic-shaped GFP-positive mononuclear cells constituted a significant stromal subpopulation in primary tumor peripheral area (PA) and metastatic tumor area (MA) microenvironment, thus implicating an invasive and metastatic role for these cells. CD11b co-expression in GFP-positive cells suggests that round/dendritic cell subpopulations are possibly BM-derived macrophages. Identification of GFP-positive mononuclear infiltrates co-expressing CD31 suggests that these cells might be BM-derived angioblasts, whereas their non-reactivity for CD34, CD105 and α-SMA implies an altered vascular phenotype distinct from endothelial cells. Significant upregulation of GFP-positive, CD31-positive and GFP/CD31 double-positive cell densities positively correlated with PA and MA (P<0.05). Conclusion: Taken together, in vivo evidence of traceable GFP-positive BMDCs in primary and metastatic tumor microenvironment suggests that recruited BMDCs might partake in cancer invasion and metastasis, possess multilineage potency and promote angiogenesis.
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Affiliation(s)
- Hotaka Kawai
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Hidetsugu Tsujigiwa
- Department of Life Science, Faculty of Science, Okayama University of Science, Okayama, Japan
| | - Chong Huat Siar
- Department of Oral and Maxillofacial Clinical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Keisuke Nakano
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Kiyofumi Takabatake
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Masae Fujii
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Mei Hamada
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Ryo Tamamura
- Department of Histology, Nihon University School of Dentistry at Matsudo, Japan
| | - Hitoshi Nagatsuka
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
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Abstract
Inflammatory bowel diseases (IBDs) are debilitating conditions that result in intestinal damage due to chronic inflammation. In addition, the perpetual state of inflammation predisposes individuals to the development of colitis-associated cancer. Because of the immense immune cell infiltration into colon, cytokines produced by immune cells are major players in the initiation and progression of IBD and colitis-associated cancer. In this review, we will explore the functions of many key cytokines and their roles in IBD and colitis-associated cancer, as well as their influences on the immune system and stromal cells. Finally, we will briefly discuss current therapies and current clinical trials targeting cytokines in IBD.
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Sun T, Gao GZ, Li RF, Li X, Li DW, Wu SS, Yeo AE, Jin B. Bone marrow-derived mesenchymal stem cell transplantation ameliorates oxidative stress and restores intestinal mucosal permeability in chemically induced colitis in mice. Am J Transl Res 2015; 7:891-901. [PMID: 26175850 DOI: pmid/26175850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Accepted: 05/13/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Ulcerative colitis (UC) can be viewed as an autoimmune disease. Bone marrow-derived mesenchymal stem cells (MSCs) with its regenerative, cellular multi-lineage and immunomodulatory abilities can influence the repair of damaged tissues in UC. This study investigated the effects of MSCs transplantation on the mice intestinal barrier in response to oxidative stress injury. METHODS Colitis was induced by daily consecutive administration of 5% dextran sulfate sodium (DSS) solution for 7 days. Male murine MSCs were isolated and transplanted into female mice via injection in the tail vein. Serum and colon specimens were collected at 12 h, 24 h, 3 d, 7 d and 14 d after injection. Serum levels of D-lactate (D-LAC), diamine oxidase (DAO), colonic levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were quantified. The SRY protein of the male sex determinant gene expression and E-cadherin were also ascertained intracellularly. RESULTS Three days after receiving male MSCs transplantation, SRY protein expression was detected. The quantity increased on successive days. Serum levels of D-LAC and DAO, colonic MDA and SOD normalized in a shorter time period compared to controls (p<0.05). Not surprisingly, histological regeneration of tissue and E-cadherin expression in the colon of MSCs transplanted mice also occurred in a shorter time period than controls. CONCLUSIONS Transplanted MSCs restored mucosal permeability, and minimized oxidative stress related injury.
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Affiliation(s)
- Tao Sun
- Naval General Hospital Beijing, China
| | | | | | - Xin Li
- Naval General Hospital Beijing, China
| | - Da-Wei Li
- Naval General Hospital Beijing, China
| | | | | | - Bo Jin
- Department of Gastroenterology, The 309th Hospital of People's Liberation Army China
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Abstract
Inflammatory bowel disease (IBD) is a group of chronic non-specific inflammatory disease with unknown etiology; it is associated with genetic factors, immune factors, intestinal flora, infection, and other factors. In recent years, mesenchymal stem cells (MSCs) have attracted more and more attention in the treatment of IBD, and the therapeutic effects may be associated with their antiinflammatory and immunomodulatory effects as well as intestinal epithelium reconstruction. In this article, we will review the causes of IBD and possible mechanisms of MSCs in treating IBD.
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Fawzy SA, El-Din Abo-Elnou RK, Abd-El-Maksoud El-Deeb DF, Yousry Abd-Elkader MM. The possible role of mesenchymal stem cells therapy in the repair of experimentally induced colitis in male albino rats. Int J Stem Cells 2014; 6:92-103. [PMID: 24386553 DOI: 10.15283/ijsc.2013.6.2.92] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/29/2013] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND OBJECTIVES Colitis is inflammation of the colon which can be transmural or confined to the mucosa. Colitis may be acute or chronic. In case of serious intestinal discontinuity of epithelium, the regeneration capacity of local stem cells is not enough to complete tissue repair. Bone marrow mesenchymal stem cells (BM-MSCs) migrate into the gastrointestinal wall, where they may contribute to the repair progress. The present study aimed at evaluating the possible therapeutic effect of MSCs on induced colitis in albino rat. METHODS AND RESULTS Twenty male albino rats were divided into 3 groups (control, colitis, MSCs), control group (4 rats), colitis group (8 rats) received once intra-rectal injection of 2 ml of 3% acetic acid. MSCs therapy group (8 rats) injected with MSCs 24 hours after colitis induction. In each group, rats were subdivided into subgroups (a & b). Subgroup (a) corresponds to rats sacrificed 3 days and subgroup (b) corresponds to rats sacrificed 10 days after colitis induction. Isolation and culture of MSCs from rat bone marrow were performed. Colon sections were examined using light and fluorescent microscopy. Colon specimens were subjected to histological, morphometric and statistical studies. In colitis group, ulceration, loss of surface columnar epithelium, disturbed crypts architecture with few goblet cells and huge lymphatic nodule piercing the muscularis mucosa were reported. In stem cell therapy group, MSCs stimulate colonic repair through differentiation into several cells and dampen the inflammation. CONCLUSIONS MSCs represent future therapeutic hopes for intestinal injury and chronic intestinal inflammatory states.
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Affiliation(s)
- Sohair Ahmed Fawzy
- Department of Histology, Faculty of Medicine, Cairo University, Cairo, Egypt
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Linard C, Busson E, Holler V, Strup-Perrot C, Lacave-Lapalun JV, Lhomme B, Prat M, Devauchelle P, Sabourin JC, Simon JM, Bonneau M, Lataillade JJ, Benderitter M. Repeated autologous bone marrow-derived mesenchymal stem cell injections improve radiation-induced proctitis in pigs. Stem Cells Transl Med 2013; 2:916-927. [PMID: 24068742 PMCID: PMC3808206 DOI: 10.5966/sctm.2013-0030] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Accepted: 06/04/2013] [Indexed: 01/06/2023] Open
Abstract
The management of proctitis in patients who have undergone very-high-dose conformal radiotherapy is extremely challenging. The fibrosis-necrosis, fistulae, and hemorrhage induced by pelvic overirradiation have an impact on morbidity. Augmenting tissue repair by the use of mesenchymal stem cells (MSCs) may be an important advance in treating radiation-induced toxicity. Using a preclinical pig model, we investigated the effect of autologous bone marrow-derived MSCs on high-dose radiation-induced proctitis. Irradiated pigs received repeated intravenous administrations of autologous bone marrow-derived MSCs. Immunostaining and real-time polymerase chain reaction analysis were used to assess the MSCs' effect on inflammation, extracellular matrix remodeling, and angiogenesis, in radiation-induced anorectal and colon damages. In humans, as in pigs, rectal overexposure induces mucosal damage (crypt depletion, macrophage infiltration, and fibrosis). In a pig model, repeated administrations of MSCs controlled systemic inflammation, reduced in situ both expression of inflammatory cytokines and macrophage recruitment, and augmented interleukin-10 expression in rectal mucosa. MSC injections limited radiation-induced fibrosis by reducing collagen deposition and expression of col1a2/col3a1 and transforming growth factor-β/connective tissue growth factor, and by modifying the matrix metalloproteinase/TIMP balance. In a pig model of proctitis, repeated injections of MSCs effectively reduced inflammation and fibrosis. This treatment represents a promising therapy for radiation-induced severe rectal damage.
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Affiliation(s)
- Christine Linard
- Institute of Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France
| | - Elodie Busson
- Research and Cell Therapy Department, Military Blood Transfusion Center, Percy Military Hospital, Clamart, France
| | - Valerie Holler
- Institute of Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France
| | - Carine Strup-Perrot
- Institute of Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France
| | | | - Bruno Lhomme
- Institute of Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France
| | - Marie Prat
- Research and Cell Therapy Department, Military Blood Transfusion Center, Percy Military Hospital, Clamart, France
| | - Patrick Devauchelle
- Centre of Radiotherapy Scanner, National Veterinary School, Maison-Alfort, France
| | | | - Jean-Marc Simon
- Department of Radiation Oncology, Pitie-Salpetriere University Hospital, Paris, France
| | - Michel Bonneau
- Centre of Research in Interventional Imaging, Institut National de la Recherche Agronomique, Jouy-en-Josas, France
| | - Jean-Jacques Lataillade
- Research and Cell Therapy Department, Military Blood Transfusion Center, Percy Military Hospital, Clamart, France
| | - Marc Benderitter
- Institute of Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France
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Sun Z, Gong X, Zhu H, Wang C, Xu X, Cui D, Qian W, Han X. Inhibition of Wnt/β-Catenin Signaling Promotes Engraftment of Mesenchymal Stem Cells to Repair Lung Injury. J Cell Physiol 2013; 229:213-24. [DOI: 10.1002/jcp.24436] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Accepted: 07/15/2013] [Indexed: 11/05/2022]
Affiliation(s)
- Zhaorui Sun
- Immunology and Reproductive Biology Laboratory; Medical College of Nanjing University; Nanjing PR China
- Jiangsu Key Laboratory of Molecular Medicine; Nanjing PR China
- State Key Laboratory of Analytical Chemistry for Life Science; Nanjing University; Nanjing PR China
| | - Xuemin Gong
- Immunology and Reproductive Biology Laboratory; Medical College of Nanjing University; Nanjing PR China
- Jiangsu Key Laboratory of Molecular Medicine; Nanjing PR China
- State Key Laboratory of Analytical Chemistry for Life Science; Nanjing University; Nanjing PR China
| | - Huiming Zhu
- Immunology and Reproductive Biology Laboratory; Medical College of Nanjing University; Nanjing PR China
- Jiangsu Key Laboratory of Molecular Medicine; Nanjing PR China
- State Key Laboratory of Analytical Chemistry for Life Science; Nanjing University; Nanjing PR China
| | - Cong Wang
- Immunology and Reproductive Biology Laboratory; Medical College of Nanjing University; Nanjing PR China
- Jiangsu Key Laboratory of Molecular Medicine; Nanjing PR China
- State Key Laboratory of Analytical Chemistry for Life Science; Nanjing University; Nanjing PR China
| | - Xiaomeng Xu
- Immunology and Reproductive Biology Laboratory; Medical College of Nanjing University; Nanjing PR China
- Jiangsu Key Laboratory of Molecular Medicine; Nanjing PR China
- State Key Laboratory of Analytical Chemistry for Life Science; Nanjing University; Nanjing PR China
| | - Di Cui
- Immunology and Reproductive Biology Laboratory; Medical College of Nanjing University; Nanjing PR China
- Jiangsu Key Laboratory of Molecular Medicine; Nanjing PR China
- State Key Laboratory of Analytical Chemistry for Life Science; Nanjing University; Nanjing PR China
| | - Weiping Qian
- State Key Laboratory of Bioelectronics; Southeast University; Nanjing PR China
| | - Xiaodong Han
- Immunology and Reproductive Biology Laboratory; Medical College of Nanjing University; Nanjing PR China
- Jiangsu Key Laboratory of Molecular Medicine; Nanjing PR China
- State Key Laboratory of Analytical Chemistry for Life Science; Nanjing University; Nanjing PR China
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CXCL12/CXCR4 axis promotes mesenchymal stem cell mobilization to burn wounds and contributes to wound repair. J Surg Res 2013; 183:427-34. [DOI: 10.1016/j.jss.2013.01.019] [Citation(s) in RCA: 114] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Revised: 12/16/2012] [Accepted: 01/10/2013] [Indexed: 12/29/2022]
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Su H, Cong X, Liu YL. Transplantation of granulocytic myeloid-derived suppressor cells (G-MDSCs) could reduce colitis in experimental murine models. J Dig Dis 2013; 14:251-8. [PMID: 23279711 DOI: 10.1111/1751-2980.12029] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Myeloid-derived suppressor cells (MDSCs) are a group of myeloid cells expressing CD11b and Gr-1 marker in mice and comprise at least two subsets: granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (M-MDSCs). This study aimed to evaluate the therapeutic efficacy of transplantation of G-MDSC subsets from normal mice to colitis mice. METHODS Murine colitis model was induced by the intrarectal administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS). The mice were divided into four groups: control group, TNBS-induced colitis, TNBS-induced colitis plus normal saline injection and TNBS-induced colitis plus bone marrow-derived G-MDSCs injection (transplantation group). G-MDSCs were sorted and enriched via magnetic-activated cell sorting (MACS) program, the purity of the sorted cells was then identified using flow cytometry analysis. Sex cross-transplantation of dominant G-MDSCs was applied from normal mice to colitis models using i.v. injection. Changes of body weight, survival rate, myeloperoxidase (MPO) activity were monitored and macroscopic and microscopic injury scores are calculated. Donor cell Y chromosomes were assessed by in situ hybridization to assess reconstitutions. RESULTS After the transplantation of bone marrow-derived G-MDSCs from normal mice to colitis models, recipient mice showed increased survival rate, decreased macroscopic and microscopic injury scores and MPO activity, as well as lowered concentration of serum interleukin-6. Y chromosomes staining displayed colonization of donor cells of liver, spleen and colon tissues. CONCLUSION Bone marrow-derived G-MDSCs are effective in the improvement of murine colitis, but its effect in human needs further investigation.
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Affiliation(s)
- Hui Su
- Department of Gastroenterology, Peking University People's Hospital, Beijing, China
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He XW, He XS, Lian L, Wu XJ, Lan P. Systemic infusion of bone marrow-derived mesenchymal stem cells for treatment of experimental colitis in mice. Dig Dis Sci 2012; 57:3136-44. [PMID: 22752635 DOI: 10.1007/s10620-012-2290-5] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2011] [Accepted: 06/11/2012] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS The anti-inflammatory and reparative properties of mesenchymal stem cells (MSCs) make them a promising tool for treating immune-mediated and inflammatory disorders. However, whether MSCs can be used for treatment of inflammatory bowel disease (IBD) still remains unclear. In this study, a dextran sulfate sodium (DSS)-induced mouse colitis model was used to test the hypothesis that infused bone marrow-derived MSCs could exert anti-inflammatory effects against experimental colitis. METHODS DSS-induced colitis mice were injected with 1 × 10(6) MSCs [in phosphate-buffered saline (PBS)] via the tail vein. Control colitis mice received PBS alone. To trace the injected cells in vivo, MSCs were labeled with chloromethyl-benzamidodialkylcarbocyanine (CM-DiI). On day 15 of the experiment, the colon was sectioned and examined for histopathological changes. Pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β] in the inflamed colon were analyzed by real-time reverse-transcription polymerase chain reaction (RT-PCR). Serum values of TNF-α in mice were evaluated quantitatively by enzyme-linked immunosorbent assay (ELISA) analysis. RESULTS DSS-induced colitis showed symptoms similar to ulcerative colitis in humans, including body weight loss, bloody diarrhea, mucosal ulceration, and shortening of the colon. Bone marrow-derived MSCs significantly ameliorated the clinical and histopathologic severity of DSS colitis compared with non-MSC control. Pro-inflammatory cytokines in both the inflamed colon (TNF-α, IL-1β) and serum (TNF-α) were downregulated in MSC-treated mice in contrast to control. CM-DiI-labeled MSCs accumulated in inflamed regions of the colon, mainly in the submucosa. CONCLUSIONS Systemic infusion of bone marrow-derived MSCs may exert therapeutic efficacy on acute DSS-induced colitis in mice through their anti-inflammatory effects, which demonstrates the feasibility of using bone marrow-derived MSCs to treat IBD.
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Affiliation(s)
- Xiao-Wen He
- Department of Colorectal and Anal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Rd, Guangzhou, 510655, Guangdong Province, People's Republic of China.
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Mátrai Z, Pesthy P, Gulyás G, Szabó E, Bartal A, Kásler M. [Autologous fat transplantation in the modern reconstructive surgery of breast cancer]. Orv Hetil 2012; 153:1816-31. [PMID: 23146782 DOI: 10.1556/oh.2012.29487] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Autologous fat transplantation is often used in aesthetic plastic surgery, and is recently becoming increasingly popular in the reconstruction of soft tissue defects following oncological surgery. A still not standardized technique of fat transplantation for breast cancer reconstruction is rapidly getting popular. The procedure is not a passive volume replacement, but transplantation of biologically active tissue bearing endocrine, paracrine, exocrine functions and containing fat-derived stem cells, which in the tumorous environment raises many questions in relation to the oncological safety and diagnostic follow-up. Although long-term results based on prospective, randomized studies are not yet available, published clinical experience is promising and reveals an effective and surgically safe procedure if used with appropriate indications and techniques. The authors conducted a broad review of the literature, presenting indications, technique, molecular interactions, and potential risks of the clinical results of autologous fat transplantation in the breast cancer reconstructive surgery. The authors initiated that breast and plastic surgeons should promote adequate long term follow-up of breast cancer patients who underwent breast reconstruction with autologous fat transplantation by the establishment of national registries.
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Affiliation(s)
- Zoltán Mátrai
- Országos Onkológiai Intézet Daganatsebészeti Központ, Emlő- és Lágyrész-sebészeti Osztály, Budapest.
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Hogan NM, Dwyer RM, Joyce MR, Kerin MJ. Mesenchymal stem cells in the colorectal tumor microenvironment: recent progress and implications. Int J Cancer 2012; 131:1-7. [PMID: 22290082 DOI: 10.1002/ijc.27458] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Revised: 12/20/2011] [Accepted: 01/12/2012] [Indexed: 01/06/2025]
Abstract
Mesenchymal stem cells (MSCs) are nonhematopoietic multipotent adult stem cells. They have been shown to have a natural tropism for many tumors types, including colorectal, and are capable of escaping host immune surveillance. MSCs are known to engraft at tumors and integrate into their architecture, potentially as carcinoma-associated fibroblasts. In contrast with other malignancies, our understanding of the interactions between colorectal cancer cells and MSCs remains limited. Considering the established importance of inflammation in the colorectal cancer primary tumor microenvironment and the role of stromal cells in this process, there is a potential wealth of information to be gleaned from further investigation of interactions between these cell populations. Epithelial-mesenchymal transition is central to colorectal cancer progression and MSCs have also been implicated in this process. This review explores the current knowledge (both in vitro and in vivo) of interactions between colorectal cancer cells and MSCs. It highlights potential effects of cell source, number and ratio on outcome of in vivo studies and explores strategies to more accurately explore their role in the primary tumor microenvironment. As our understanding of the underlying molecular processes in colorectal cancer develops, elucidation of these interactions will be central to development of novel therapeutic strategies for this prevalent disease.
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Affiliation(s)
- Niamh M Hogan
- Discipline of Surgery, School of Medicine, National University of Ireland, Galway, Ireland
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15
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Godoi DF, Cardoso CR, Silva MJB, Ferraz DB, Provinciatto PR, Cunha FDQ, da Silva JS, Voltarelli JC. Reappraisal of total body irradiation followed by bone marrow transplantation as a therapy for inflammatory bowel disease. Immunobiology 2012; 218:317-24. [PMID: 22771114 DOI: 10.1016/j.imbio.2012.05.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Accepted: 05/16/2012] [Indexed: 01/14/2023]
Abstract
The main current therapies for inflammatory bowel diseases (IBD) are aimed at controlling the exacerbated inflammation in the gut. Although these therapies have been successful, they are not curative and it is not possible to predict whether a beneficial response will occur or which patients will be refractory to the treatment. Total body irradiation (TBI) associated with chemotherapy is the first choice in the treatment of some hematological disorders and is an applicable option in the preparation of patients with hematologic diseases for hematopoietic stem cell transplantation. Then, in this study we investigated the association of TBI as immunosuppressive therapy and bone marrow cell (BMC) transplantation as a strategy to induce colitis recovery and immune reconstitution in the TNBS model of intestinal inflammation. TNBS mice treated with TBI associated with BMC transplantation presented elevated gain of weight and an overall better outcome of the disease when compared to those treated only with TBI. In addition, TBI associated or not with BMC reduced the frequency of inflammatory cells in the gut and restored the goblet cell counts. These results were accompanied by a down regulation in the production of inflammatory cytokines in the colon of mice treated with TBI alone or in association with BMC transplantation. The BMC infused were able to repopulate the ablated immune system and accumulate in the site of inflammation. However, although both treatments (TBI or TBI+BMC) were able to reduce gut inflammation, TBI alone was not enough to fully restore mice weight and these animals presented an extremely reduced survival rate when their immune system was not promptly reconstituted with BMC transplantation. Finally, these evidences suggest that the BMC transplantation is an efficient strategy to reduce the harmful effects of TBI in the colitis treatment, suggesting that radiotherapy may be an important immunosuppressive therapy in patients with IBD, by modulating the local inflammatory response.
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Affiliation(s)
- Dannielle Fernandes Godoi
- Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
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Secretion of rat tracheal epithelial cells induces mesenchymal stem cells to differentiate into epithelial cells. Cell Biol Int 2011; 36:169-75. [DOI: 10.1042/cbi20110121] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
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Valcz G, Krenács T, Sipos F, Patai AV, Wichmann B, Leiszter K, Tóth K, Balogh Z, Csizmadia A, Hagymási K, Masszi T, Molnár B, Tulassay Z. Lymphoid aggregates may contribute to the migration and epithelial commitment of bone marrow-derived cells in colonic mucosa. J Clin Pathol 2011; 64:771-775. [PMID: 21653659 DOI: 10.1136/jclinpath-2011-200022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
AIMS Colonic inflammation is followed by regeneration supported by bone marrow-derived cells (BMDCs) including multipotent cells. They migrate to the colonic epithelial layer and may transdifferentiate into epithelial-like cells or keep their stem cell characteristics and produce progenies. The aim was to study the role of lymphoid aggregates in the migration and transition of BMDCs in both healthy colons and non-specific colitis (NSC). METHODS Samples of normal colon (n=5) and NSC (n=5) from female patients who were initially transplanted with male bone marrow were studied. After detecting XY chromosomes using fluorescent in situ hybridisation, tissue sections were digitalised, the coverslips were eliminated and the samples were double stained for CD45 and cytokeratin with immunofluorescence. Then CDX2 expression, as a sign of intestinal epithelial commitment of Musashi-1+ stromal BMDCs, was also tested with both immunoperoxidase and parallel immunofluorescence stainings. The slides were digitalised again and analysed simultaneously. RESULTS A significant increase in intraepithelial CD45-BMDCs was found in regions adjacent to lymphoid aggregates (median: 1.01) compared with healthy epithelial regions (median: 0.0175) or NSC (median: 0.04) samples. The stromal Musashi-1+ cells were positive for CDX2 as well, as a sign of epithelial differentiation. The CDX2+ cells bearing the Y chromosome proved the epithelial commitment of several stromal BMDCs. CONCLUSION Elevated number of intraepithelial CD45-BMDCs at lymphoid aggregates suggests that BMDCs play a role in epithelial regeneration and that lymphoid aggregates serve as their migration route.
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Affiliation(s)
- Gábor Valcz
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
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Pearl RA, Leedham SJ, Pacifico MD. The safety of autologous fat transfer in breast cancer: lessons from stem cell biology. J Plast Reconstr Aesthet Surg 2011; 65:283-8. [PMID: 21820375 DOI: 10.1016/j.bjps.2011.07.017] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2011] [Accepted: 07/09/2011] [Indexed: 12/26/2022]
Abstract
Autologous fat grafting is versatile tool in plastic surgery and is increasing used for reconstruction following breast conserving surgery for breast cancer. Part of the reconstructive qualities of the transferred fat may be due to the presence of adipose derived mesenchymal stem cells (ADMSC) playing an angiogenic and an adipogenic role. In this context it must be considered if autologously engrafted fat tissue could contribute to carcinogenesis following breast conserving surgery. In this article we review the current stem cell biology evidence on engraftment, transdifferentiation and potential carcinogenic contribution in the breast and other solid organ stem cell niches in an attempt to highlight possible areas of concern.
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Affiliation(s)
- Robert A Pearl
- Department of Plastic and Reconstructive Surgery, Queen Victoria Hospital, East Grinstead, West Sussex, United Kingdom.
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Mifflin RC, Pinchuk IV, Saada JI, Powell DW. Intestinal myofibroblasts: targets for stem cell therapy. Am J Physiol Gastrointest Liver Physiol 2011; 300:G684-96. [PMID: 21252048 PMCID: PMC3094146 DOI: 10.1152/ajpgi.00474.2010] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The subepithelial intestinal myofibroblast is an important cell orchestrating many diverse functions in the intestine and is involved in growth and repair, tumorigenesis, inflammation, and fibrosis. The myofibroblast is but one of several α-smooth muscle actin-positive (α-SMA(+)) mesenchymal cells present within the intestinal lamina propria, including vascular pericytes, bone marrow-derived stem cells (mesenchymal stem cells or hematopoietic stem cells), muscularis mucosae, and the lymphatic pericytes (colon) and organized smooth muscle (small intestine) associated with the lymphatic lacteals. These other mesenchymal cells perform many of the functions previously attributed to subepithelial myofibroblasts. This review discusses the definition of a myofibroblast and reconsiders whether the α-SMA(+) subepithelial cells in the intestine are myofibroblasts or other types of mesenchymal cells, i.e., pericytes. Current information about specific, or not so specific, molecular markers of lamina propria mesenchymal cells is reviewed, as well as the origins of intestinal myofibroblasts and pericytes in the intestinal lamina propria and their replenishment after injury. Current concepts and research on stem cell therapy for intestinal inflammation are summarized. Information about the stem cell origin of intestinal stromal cells may inform future stem cell therapies to treat human inflammatory bowel disease (IBD).
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Affiliation(s)
| | | | | | - D. W. Powell
- Departments of 1Internal Medicine and ,2Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas
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Valcz G, Krenács T, Sipos F, Leiszter K, Tóth K, Balogh Z, Csizmadia A, Muzes G, Molnár B, Tulassay Z. The role of the bone marrow derived mesenchymal stem cells in colonic epithelial regeneration. Pathol Oncol Res 2011; 17:11-16. [PMID: 20405350 DOI: 10.1007/s12253-010-9262-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2009] [Accepted: 03/22/2010] [Indexed: 02/08/2023]
Abstract
Bone marrow derived mesenchymal stem cells (BM-MSCs) take part in the colonic mucosal regeneration. They are multipotent cells, which can be identified with both negative (i.e. CD13, CD 14, CD45, c-Kit, major histocompatibility complex /MHC class I and II) and positive (i.e. CD54 (ICAM1), CD133, CD146 (MCAM), CD166, Flk-1, Sca-1, Thy-1, stage-specific antigen I /SSEA-I and Musashi-1, HLA class I) markers. These cells can repopulate the gastrointestinal mucosa as they may differentiate into stromal- (i.e. myofi-broblast) or epithelial-like (Paneth-, epithel-, goblet or enteroendocrin) cells without proliferation. During the mesenchymal to epithelial transition (MET) stem cells enter the epithelial layer and take up epithelial cell-like properties. Rarely BM-MSCs may retain their stem cell characteristics and are capable of producing progeny. The isolated lymphoid aggregates may serve as a platform from where BM-MSCs migrate to the nearby crypts as mediated by several chemoattractant proteins, which are expressed in injured tissue. The number of BM-MSCs is influenced by the degree of inflammation. In this review we summarize the current information about the role of BM-MSCs in the repair progress of injured colonic epithelium and their potential clinical applications.
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Affiliation(s)
- Gábor Valcz
- 2nd Department of Internal Medicine, Cell Analysis Laboratory, Semmelweis University, Szentkiralyi Street 46, 1088 Budapest, Hungary.
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Abstract
PURPOSE OF REVIEW Stem cell therapy for intestinal diseases is an emerging area in clinical gastroenterology. We will review recent literature regarding mesenchymal stem cells, which have been utilized in preclinical models and are now headed for clinical trials in several gastrointestinal diseases including inflammatory bowel disease. RECENT FINDINGS Important studies over the last 2 years have made significant inroads into understanding the mechanisms of action of these cell types. The two major competing hypotheses are that mesenchymal stem cells home to areas of injury where they repair based on their stem cell activity or that mesenchymal stem cells act as a source of secreted factors that stimulate repair and inhibit inflammation. SUMMARY Mesenchymal stem cells show promise for therapy in a number of intestinal diseases. Further understanding of their mechanism of action should improve our ability to use them therapeutically.
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22
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Myogenic lineage differentiated mesenchymal stem cells enhance recovery from dextran sulfate sodium-induced colitis in the rat. J Gastroenterol 2011; 46:143-52. [PMID: 20848145 DOI: 10.1007/s00535-010-0320-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2010] [Accepted: 08/13/2010] [Indexed: 02/04/2023]
Abstract
BACKGROUND Although mounting evidence implicates mesenchymal stem cells (MSCs) in intestinal tissue repair, uncertainty remains concerning the distribution, function, and fate of repopulating MSCs in recipient colonic tissues. Therefore, we investigated the role of transplanted MSCs in the repair phase of DSS colitis. METHODS LacZ-labeled rat MSCs were transplanted into rats with colitis induced by 4% DSS on day 2. Regular water replaced the DSS solution on day 6. Therapeutic effect was evaluated on day 9 by clinicopathologic and growth factor/cytokine expression profiles. We analyzed the Notch signaling pathway by Western blotting and characterized immunofluorescence of lacZ-labeled MSCs with confocal laser microscopy. In vivo differentiation of MSC was confirmed by transmission electron microscopy (TEM). RESULTS Recovery of colitis was modestly but significantly promoted by MSC transplantation due to proceeding cell cycle and inhibiting apoptosis in the epithelia. Tgfa mRNA expression increased significantly, while Notch signaling was inhibited in the colonic tissues with MSC transplantation. β-Galactosidase-positive cells, which expressed α-SMA, desmin, and vimentin, were infrequently detected in the lamina propria stroma. DSS exposure in vitro proved to be the most potent inducer for α-SMA in MSCs where TEM demonstrated myogenic lineage differentiation. CONCLUSIONS We found that MSCs transplantation modestly promoted the repair of DSS colitis. The donor-derived MSCs were likely reprogrammed to differentiate to myogenic lineage cells by cues from the micro milieu. Further characterization of these cells is warranted as a basis for applying cell-based therapy for inflammatory bowel disease.
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23
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Wu WY, Chen QK. Mesenchymal stem cells engraftment in the injured intestine of mice. Shijie Huaren Xiaohua Zazhi 2010; 18:3129-3133. [DOI: 10.11569/wcjd.v18.i29.3129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the engraftment of murine bone marrow mesenchymal stem cells (MSCs) in the irradiated intestine of mice to provide some clues about the mechanism of intestine epithelium healing and lay an experimental foundation for treatment of intestine diseases by intravenous transplantation of MSCs.
METHODS: MSCs from male mice were isolated, expanded, identified, suspended in sterile normal saline (1 × 106 cells/mL), and slowly infused into irradiated female mice via the tail vein. Meanwhile, a group of irradiated female mice receiving an equal volume of sterile normal saline were used as controls. For tracing male MSC residence in the intestine after intravenous transplantation, in situ hybridization (ISH) was used to detect the Sry gene on the Y chromosome.
RESULTS: In the transplantation group, ISH analysis revealed the presence of male donor MSCs in the submucosa of the intestine of female mice, but not in the mucosal epithelium. At week 1 after cell transplantation, Sry-positive cells were scattered around the crypt, with a percentage of 19.48% ± 5.01%. At week 2, this percentage rose to 30.86% ± 12.14%, significantly higher than that at week 1 (P < 0.05). However, there was no significant difference in the percentage of Sry-positive cells between at week 2 and week 4 (week 4: 35.95% ± 11.98%, P > 0.05). In the control group, no Sry-positive cells were found.
CONCLUSION: After MSCs were transplanted into mice, they were attracted to and retained in the irradiated intestine and colonized in the intestinal submucosa.
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Hutchinson L, Stenstrom B, Chen D, Piperdi B, Levey S, Lyle S, Wang TC, Houghton J. Human Barrett's adenocarcinoma of the esophagus, associated myofibroblasts, and endothelium can arise from bone marrow-derived cells after allogeneic stem cell transplant. Stem Cells Dev 2010; 20:11-7. [PMID: 20677919 DOI: 10.1089/scd.2010.0139] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
This study characterizes the contribution of bone marrow-derived cells (BMDCs) to Barrett's adenocarcinoma of the esophagus using a mouse surgical model of disease and human specimens. Transplantation of bone marrow expressing beta galactosidase into a wild-type mouse, followed by surgical esophagojejunostomy, allowed tracking of BMDCs into the surgical anastomosis and resulting Barrett's metaplasia. Human tissue from a male patient who had been transplanted with female bone marrow and later developed esophageal adenocarcinoma allowed us to tract donor-derived cells into the tumor. Using a combination of antibodies directed against beta-galactosidase (animal studies) and X/Y fluorescent in situ hybridization (FISH) (human studies), combined with specific lineage staining directed against epithelial, fibroblast, endothelial, and leukocyte markers, we show that bone marrow cells contribute to both the epithelial and stromal component of esophageal adenocarcinoma. These findings demonstrate that BMDCs can generate cancer-associated fibroblasts as well as contribute directly to epithelial cells in cancer of the esophagus.
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Affiliation(s)
- Lloyd Hutchinson
- Department of Pathology, UMass Memorial Health Care, Worcester, MA, USA
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25
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Shaker A, Rubin DC. Intestinal stem cells and epithelial-mesenchymal interactions in the crypt and stem cell niche. Transl Res 2010; 156:180-7. [PMID: 20801415 PMCID: PMC3019104 DOI: 10.1016/j.trsl.2010.06.003] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2010] [Revised: 06/09/2010] [Accepted: 06/10/2010] [Indexed: 12/19/2022]
Abstract
The intestinal epithelium contains a rapidly proliferating and perpetually differentiating epithelium. The principal functional unit of the small intestine is the crypt-villus axis. Stem cells located in the crypts of Lieberkühn give rise to proliferating progenitor or transit amplifying cells that differentiate into the 4 major epithelial cell types. The study of adult gastrointestinal tract stem cells has progressed rapidly with the recent discovery of several putative stem cell markers. Substantial evidence suggests 2 populations of stem cells: long-term quiescent (reserved) and actively cycling (primed) stem cells. These cells are in adjoining locations and are presumably maintained by the secretion of specific proteins generated in a unique microenvironment or stem cell niche surrounding each population. The relationship between these 2 populations, as well as the cellular sources and composition of the surrounding environment, remains to be defined, and is an active area of research. In this review, we will outline progress in identifying stem cells and in defining epithelial-mesenchymal interactions in the crypt. We will summarize early advances using stem cells for therapy of gastrointestinal disorders.
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Affiliation(s)
- Anisa Shaker
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
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26
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Liu D, Wang F, Zou Z, Dong S, Shi C, Wang J, Ran X, Su Y. Long-term repopulation effects of donor BMDCs on intestinal epithelium. Dig Dis Sci 2010; 55:2182-93. [PMID: 19856101 DOI: 10.1007/s10620-009-0991-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2009] [Accepted: 09/14/2009] [Indexed: 12/09/2022]
Abstract
BACKGROUND Bone marrow-derived cells (BMDCs) have the ability to differentiate into intestinal epithelial cells after transplantation and participate in the regeneration process of damaged epithelium. AIMS To investigate whether BMDCs could differentiate into intestinal epithelium long term in chimeric mice after transplantation and without special treatment. METHODS Forty irradiated C57BL/6 mice were used. Thirty of them (group A) received transplantation of BMDCs from GFP transgenic mice, and ten (group B) received PBS. The chimeric percentage at the 14th month was examined by flow cytometry. Engraftment of BMDCs was detected by immunohistochemistry in intestinal epithelium. Immunofluorescence observation was used to detect coexpression of PCK, CD45 and Chromogranin A with GFP. BMDCs in the epithelium were observed by an immune electron microscope. The percent of GFP(+) epithelial cells was also determined by flow cytometry. RESULTS Mice in group A had a survival rate of 93.3% 1 week after transplantation. BMDCs could engraft into recipients' intestinal epithelium. These cells expressed epithelial cell marker PCK, but could not express CD45. Some of them differentiated into enteroendocrine cells expressing Chromogranin A. GFP(+) villous epithelial cells ranged from 9.41 to 16.07% in different subgroups of group A. BMDCs in epithelium developed the characteristics of enterocytes and goblet cells. GFP(+)/PCK(+) epithelial cells at the 6th month made up a proportion of 16.11% among all the isolated epithelial cells. CONCLUSIONS Long term, BMDCs could repopulate recipient's intestinal epithelium even without any special treatment, which suggests a novel insight into the maintenance of the intestinal epithelial constitution.
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Affiliation(s)
- Dengqun Liu
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, College of Preventive Medicine, Third Military Medical University, Shapingba, Chongqing, China
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Bone marrow derivation of interstitial cells of cajal in small intestine following intestinal injury. J Biomed Biotechnol 2010; 2010:164986. [PMID: 20396598 PMCID: PMC2854535 DOI: 10.1155/2010/164986] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2009] [Revised: 12/24/2009] [Accepted: 01/27/2010] [Indexed: 12/14/2022] Open
Abstract
Interstitial cells of Cajal (ICCs) in gastrointestinal tract are specialized cells serving as pacemaker cells. The origin of ICCs is currently not fully characterized. In this work, we aimed to study whether bone marrow-derived cells (BMDCs) could contribute to the origin of ICCs in the muscular plexus of small intestine using GFP-C57BL/6 chimeric mice.Engraftment of BMDCs in the intestine was investigated for GFP expression. GFP positive bone marrow mononuclear cells reached a proportion of 95.65% ± 3.72% at different times in chimerism. Donor-derived cells distributed widely in all the layers of the gastrointestinal tract. There were GFP positive BMDCs in the myenteric plexus, which resembled characteristics of ICCs, including myenteric location, c-Kit positive staining, and ramified morphology. Donor-derived ICCs in the myenteric plexus contributed to a percentage ranging 9.25% ± 4.9% of all the ICCs in the myenteric plexus. In conclusion, here we described that donor-derived BMDCs might differentiate into gastrointestinal ICCs after radiation injury, which provided an alternative source for the origin of the ICCs in the muscular plexus of adult intestine. These results further identified the plasticity of BMDCs and indicated therapeutic implications of BMDCs for the gastrointestinal dysmotility caused by ICCs disorders.
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28
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El-Menoufy H, Aly LAA, Aziz MTA, Atta HM, Roshdy NK, Rashed LA, Sabry D. The role of bone marrow-derived mesenchymal stem cells in treating formocresol induced oral ulcers in dogs. J Oral Pathol Med 2010; 39:281-9. [PMID: 19804505 DOI: 10.1111/j.1600-0714.2009.00819.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs), a subpopulation of adult somatic stem cells, are an attractive stem cell source in regenerative medicine because of their multipotentiality. In this study, the effects of MSCs transplantation on oral ulcer healing were examined. METHODS Mesenchymal stem cells were isolated from bone marrow aspirates of dogs by dish adherence and expanded in culture. Oral ulcers were induced by topical application of formocresol in the oral cavity of dogs. Either autologous MSCs or vehicle (saline) was injected around the ulcer. The healing process of the ulcer was monitored clinically and histopathologically. Gene expression of vascular endothelial growth factor (VEGF) was detected in MSCs by reverse transcription-polymerase chain reaction. Expression of VEGF and collagen genes was detected in biopsies from all ulcers. RESULTS Mesenchymal stem cells expressed mRNA for VEGF MSCs transplantation significantly accelerated oral ulcer healing compared with controls. There was increased expression of both collagen and VEGF genes in MSCs-treated ulcers compared with controls. CONCLUSION Mesenchymal stem cells transplantation may help accelerate oral ulcer healing, possibly through the induction of angiogenesis by VEGF together with increased intracellular matrix formation as detected by increased collagen gene expression.
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Affiliation(s)
- H El-Menoufy
- Department of Periodontology, Faculty of Dentistry, Misr University of Science and Technology, Egypt
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29
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Godoi DF, Cardoso CR, Ferraz DB, Provinciatto PR, Cunha FQ, Silva JS, Voltarelli JC. Hematopoietic SCT modulates gut inflammation in experimental inflammatory bowel disease. Bone Marrow Transplant 2010; 45:1562-71. [PMID: 20228850 DOI: 10.1038/bmt.2010.6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Hematopoietic SCT (HSCT) and high-dose chemotherapy are being explored as therapy for various human refractory immune-mediated conditions, including inflammatory bowel diseases (IBD). Nevertheless, the exact immunological mechanisms by which the BM cells (BMCs) or immunosuppression provide remission from these diseases is not yet clear. In this work, we investigated the role of these therapies in the modulation of gut mucosal inflammation in an experimental model of IBD. Colitis was induced in mice by 2,4,6-trinitrobenzenesulfonic acid and after CY was administered (200 mg/kg) alone (CY group) or followed by BMCs infusion (HSCT group). Animals were followed for 60 days. Both HSCT and CY reduced the histopathological features of colitis significantly. Infused cells were localized in the gut, and a marked decrease of CD4(+) leukocytes in the inflammatory infiltrate on days +7 and +14 and of CD8(+) cells on day +7 was found in both treatments allied to impressive reduction of proinflammatory Th1 and Th17 cytokines. Although chemotherapy alone was the best treatment regarding the induction of immunosuppressive molecules, only HSCT resulted in increased survival rates compared with the control group. Our findings indicate that high-dose CY followed by HSCT is effective in the modulation of mucosal immunity and in accelerating immune reconstitution after BMT, thus providing valuable tools to support the development and understanding of novel therapeutic strategies for IBD.
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Affiliation(s)
- D F Godoi
- Department of Internal Medicine, School of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
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30
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Uehara H, Nakagawa T, Katsuno T, Sato T, Isono A, Noguchi Y, Saito Y. Emergence of fibrocytes showing morphological changes in the inflamed colonic mucosa. Dig Dis Sci 2010; 55:253-60. [PMID: 19242798 DOI: 10.1007/s10620-009-0730-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2008] [Accepted: 01/16/2009] [Indexed: 12/12/2022]
Abstract
Fibrocytes contribute to wound healing and are uniquely defined by coexpression of hematopoietic and mesenchymal cell markers. In this study, trafficking of fibrocytes was determined in a murine model of colitis induced by administering 3% dextran sodium sulfate (DSS) for seven days. Colonic tissues were immunostained for CD45, collagen type I (Col I), and alpha-SMA. On day 0, there were no CD45(+)Col I(+) cells in colonic tissues. However, on day 7 when inflammatory cells showed remarkable accumulation, oval-shaped CD45(+)Col I(+) fibrocytes were obvious in the submucosal layer. On day 14 when colonic tissues were in the healing phase, numerous spindle-shaped CD45(+)Col I(+) fibrocytes were observed. Emergence of CD45(+)Col I(+) fibrocytes preceded the appearance of alpha-SMA(+) myofibroblasts. Oval-shaped fibrocytes recruited as early as the inflammatory phase of colitis are likely to differentiate into spindle-shaped fibrocytes in the healing phase, suggesting that fibrocytes may promote wound healing in inflamed colonic tissues.
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Affiliation(s)
- Hirotsugu Uehara
- Department of Clinical Cell Biology (F5), Graduate School of Medicine, Chiba University, Chiba-shi 260-8670, Japan
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31
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32
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Comparison of the population capacity of hematopoietic and mesenchymal stem cells in experimental colitis rat model. Transplantation 2009; 88:42-8. [PMID: 19584679 DOI: 10.1097/tp.0b013e3181a9f0a7] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE This study compares the population and repair ability of bone marrow hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) in experimental colitis (EC) rat model after allogeneic stem-cell transplantation (SCT). METHODS EC was induced by 2, 4, 6-trinitrobenzenesulfonic acid (TNBS). The HSCs, MSCs, HSCs+MSCs, derived from male Sprague-Dawley rats, were cultured and labeled with bromodeoxyuridine and then transplanted into the EC rat. The colon samples were collected for histologic evaluation at days 7, 14, and 21 posttransplantation. Immunohistochemical staining, polymerase chain reaction, and fluorescence in situ hybridization were used to detect donor stem cells population. RESULTS EC induced by TNBS had characteristics similar to those of Crohn's disease. A large number of bromodeoxyuridine- labeled HSCs or MSCs were detected on days 7, 14, and 21 posttransplantation. Sex-determining region of Y chromosomes (sry) was found in all EC regions, but not in control and normal tissues. A clear localization of Y chromosomes in the colons of EC rat was detected by fluorescence in situ hybridization. Immunohistochemical staining revealed that HSCs or MSCs had similar population ability. When HSCs and MSCs were combined, gross morphologic scores significantly improved 21 days post-SCT compared with the control without SCT, but only slightly better than that of HSCs or MSCs alone. CONCLUSIONS Allogeneic transplantation of HSCs or MSCs alone could populate in the injured regions of the colons, both showed similar population ability in the colons of the TNBS-induced EC model rats. Combination transplantation of HSCs with MSCs could improve the gross morphologic scores of EC.
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Maeng LS, Chang ED, Chae HS, Kim JS, Min JY, Sohn HS, Rho SY, Kim HK, Cho YS, Choi KY, Lee HK. [Therapeutic effect of allogenic bone marrow transplantation in acute TNBS-induced colitis]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2009; 54:20-27. [PMID: 19696546 DOI: 10.4166/kjg.2009.54.1.20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND/AIMS Bone marrow-derived cells (BMDC) contribute to tissue maintenance under many kinds of pathologic conditions. We carried out a study to see how BMDC play a role in the treatment of experimental murine colitis. METHODS We divided the animals into 3 groups and treated them with 50% ethanol (control group), 2,4,6-trinitrobenzene sulfinic acid colitis (TNBS group), and TNBS+bone marrow transplant (BMT group). To induce colitis, TNBS (5.0 mg/mouse) dissolved in 50% ethanol was injected into anus weekly for two weeks. Bone marrow transplantations were performed using bone marrow of male transgenic mouse (donor) with green fluorescence protein (GFP) into female wild type mouse (recipient) three weeks before TNBS instillation. All animals were sacrificed, and colons were extracted one week after the last TNBS instillation. We measured microscopic scores of mucosal injury and investigated the GFP expression for bone marrow engraftment. The immunostaining of vimentin and alpha-smooth muscle actin (alpha-SMA) for myofibroblasts was performed. RESULTS The score of mucosal injury in the TNBS group was much more severe than those in control, and reduced significantly by BMT (p<0.05). GFP-positive cells were almost deposited in pericryptal niche of BMT group but not at all in both control and TNBS group. Most of myofibroblasts stained with both vimentin and SMA also infiltrated into pericryptal niche. But, the number of myofibroblasts stained with vimentin and SMA in both control and TNBS group was smaller than that in BMT group. CONCLUSIONS BMDC deposited on pericryptal niche might have a significant role in repairing acute experimental murine colitis.
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Affiliation(s)
- Lee So Maeng
- Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea
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Ishii S, Tsuji S, Tsujii M, Nishida T, Watabe K, Iijima H, Takehara T, Kawano S, Hayashi N. Restoration of gut motility in Kit-deficient mice by bone marrow transplantation. J Gastroenterol 2009; 44:834-841. [PMID: 19458897 DOI: 10.1007/s00535-009-0077-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2009] [Accepted: 04/02/2009] [Indexed: 02/04/2023]
Abstract
PURPOSE Interstitial cells of Cajal (ICC) play important roles in autonomic gut motility as electrical pacemakers and mediators of neural regulation of smooth muscle functions. Insufficiency of ICC has been reported in a wide range of gut dysmotilities. Thus, restoration of ICC may be a therapeutic modality in these diseases. Here we provide evidence that transplanted bone marrow (BM) cells can restore gut dysmotility in part via transdifferentiation to ICC. METHODS Bone marrow cells obtained from Kit insufficient W/W(v) mice or syngeneic GFP-transgenic mice with wild-type Kit were transferred to W/W(v) recipients. Whole gut transit time and gastric emptying were examined 5 and 6 weeks after BM transplantation, respectively, and ICCs were identified in whole mounts, frozen sections and transmission electron immunomicroscopy of the gut smooth muscle layers using specific antibodies. RESULTS Transplantation of wild-type BM into W/W(v) mice significantly improved whole gut transit time and gastric emptying. Fluorescent immunohistochemistry revealed GFP(+)Kit(+) cells in the myenteric plexus, deep muscular plexus, and submucosal plexus smooth muscle layers of the stomach, small intestine, and colon, respectively. In the whole mounts, GFP(+)Kit(+) cells were bipolar and spindle shaped, and transmission electron immunomicroscopy showed GFP(+) cells rich in mitochondria and endoplasmic reticulum between gut smooth muscle layers, suggesting the presence of GFP(+) cells with morphological characteristics of ICC. CONCLUSIONS These results suggest that BM contains cells that may incorporate into ICC networks and improve dysmotility in W/W(v) mice. Thus, BM transplantation may become to a new therapeutic modality for gut dysmotilities due to ICC insufficiency.
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Affiliation(s)
- Shuji Ishii
- Department of Gastroenterology and Hepatology (K1), Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
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Verstappen J, Katsaros C, Torensma R, Von den Hoff JW. A functional model for adult stem cells in epithelial tissues. Wound Repair Regen 2009; 17:296-305. [DOI: 10.1111/j.1524-475x.2009.00497.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Bernardo ME, Avanzini MA, Ciccocioppo R, Perotti C, Cometa AM, Moretta A, Marconi M, Valli M, Novara F, Bonetti F, Zuffardi O, Maccario R, Corazza GR, Locatelli F. Phenotypical/functional characterization of in vitro-expanded mesenchymal stromal cells from patients with Crohn's disease. Cytotherapy 2009; 11:825-36. [PMID: 19903096 DOI: 10.3109/14653240903121260] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND AIMS Because of their capacity to modulate the immune response and promote tissue repair, mesenchymal stromal cells (MSC) represent a potential novel treatment for autoimmune/inflammatory diseases, including Crohn's disease (CD). The aim of the study was in vitro characterization of MSC from active CD patients for future clinical application. METHODS MSC from the bone marrow (BM) of seven CD patients (median age 32 years) were expanded ex vivo in the presence of 5% platelet lysate; cells were investigated for clonogenic efficiency, proliferative capacity, morphology, immunophenotype, differentiation potential, genetic stability and ability to suppress in vitro proliferation of both autologous and allogeneic lymphocytes to polyclonal mitogens. Results were compared with those of BM MSC of four healthy donors (HD). RESULTS MSC were successfully expanded from all patients. Colony-forming unit-fibroblast (CFU-F) frequency and proliferative capacity were comparable in CD and HD MSC. CD MSC showed typical spindle-shaped morphology and differentiated into osteoblasts, adipocytes and chondrocytes. Surface immunologic markers did not differ between CD and HD MSC, with the only exception of sizeable levels of HLA-DR at early culture passages [12-84% at passage (P)1] in the former. CD MSC ceased their growth at variable passages (from P8 to P25) and entered senescence without any change in morphology/proliferation rate. Array-comparative genomic hybridization demonstrated that CD MSC do not show imbalanced chromosomal rearrangements. Both CD and HD MSC inhibited in vitro proliferation of lymphocytes to mitogens. CONCLUSIONS CD MSC show biologic characteristics similar to HD MSC and can be considered for anti-inflammatory and reparative cell therapy approaches in patients with refractory disease.
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Affiliation(s)
- Maria Ester Bernardo
- Oncoematologia Pediatrica, Fondazione IRCCS Policlinico San Matteo, Università di Pavia, Pavia, Italy.
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Ishii S, Tsuji S, Tsujii M, Kanazawa Y, Nishida T, Iijima H, Yasumaru M, Irie T, Yamamoto K, Tsutsui S, Eguchi H, Kawano S, Hayashi N. Involvement of bone marrow-derived stromal cells in gastrointestinal cancer development and metastasis. J Gastroenterol Hepatol 2008; 23 Suppl 2:S242-S249. [PMID: 19120906 DOI: 10.1111/j.1440-1746.2008.05446.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND The involvement of bone marrow (BM) in tumor-stroma reactions or tumor development has not been examined in a cancer allograft, which has otherwise been appropriate for assessing therapeutic modalities. We investigated the fate of BM-derived cells in colon cancer allografts and liver metastases in mice. METHODS C57BL/6 mice were irradiated and rescued by BM transplantation from green fluorescent protein (GFP)-transgenic mice. MC38 colon cancer cells were stably transfected with the pDsRed gene in order to identify tumor cells by fluorescence. These were inoculated into the mice to generate subcutaneous allografted tumors or liver metastases. The tumors were observed under confocal microscopy and fluorescent immunohistochemistry to determine the fate of tumor versus BM-derived cells. RESULTS GFP-positive (GFP(+)) cells were consistently identified as vimentin(+), alpha-smooth muscle actin (alphaSMA)(+), spindle-shaped stromal cells in both the subcutaneous tumors and the liver metastases. GFP(+) cells of leukocyte lineage also infiltrated the tumors. Neither GFP(+) CD31(+) endothelial cells nor GFP(+) DsRed(+) cells were detected in the tumor. CONCLUSIONS BM-derived cells frequently and consistently infiltrated the tumor allografts and metastases as interstitial cells and leukocytes. Cells derived from the fusion of BM cells and tumor cells were not observed. This model may be appropriate for the clarification of the effects of anticancer therapies and the study of BM-derived cells in tumor-host interactions.
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Affiliation(s)
- Shuji Ishii
- Departments of Gastroenterology and Hepatology, Osaka University Graduate School of Medcine, Suita, Osaka, Japan
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Tanaka F, Tominaga K, Ochi M, Tanigawa T, Watanabe T, Fujiwara Y, Ohta K, Oshitani N, Higuchi K, Arakawa T. Exogenous administration of mesenchymal stem cells ameliorates dextran sulfate sodium-induced colitis via anti-inflammatory action in damaged tissue in rats. Life Sci 2008; 83:771-9. [PMID: 18950645 DOI: 10.1016/j.lfs.2008.09.016] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2008] [Revised: 09/11/2008] [Accepted: 09/17/2008] [Indexed: 02/06/2023]
Abstract
AIMS Mesenchymal stem cells (MSCs) may modulate inflammatory responses resulting in improvement in inflammatory diseases, as well as tissue regeneration via cellular differentiation. We examined the therapeutic effects of exogenously administered MSCs in dextran sulfate sodium (DSS)-induced colitis in rats. MAIN METHODS Experimental colitis was produced in inbred male Lewis rats by administration of 4% DSS in drinking water for 7 days. MSCs (5x10(6) cells) which were isolated from whole marrow cells and cultured in an optimal medium for MSC outgrowth were administered to the treated rats via the tail vein on days 0, 2, and 4. On day 7, we evaluated colon length, histological changes, and colonic various mRNA expressions by RT-PCR. Localization of MSCs was evaluated using a green-fluorescent cell linker dye. To evaluate the anti-inflammatory action of MSCs, we assayed LPS-induced TNF-alpha secretion in a co-culture of MSCs and monocytes (THP-1 cells) using ELISA. KEY FINDINGS MSCs reduced in bloody stools, weight loss, colon shortening, and microscopic injuries. In the rectum of MSCs-treated rats, mRNA expression of TNF-alpha, IL-1beta, and COX-2 decreased to 40, 15, and 15% of their respective control levels. MSCs significantly suppressed mRNA expression of VEGF, HGF, and b-FGF to 40, 25, and 25% of their respective control levels. Green-fluorescent-labeled MSCs were found only within the lamina propria in inflamed regions. LPS-induced TNF-alpha secretion by THP-1 cells was significantly suppressed by co-culture with MSCs dose-dependently. SIGNIFICANCE We conclude that exogenous MSCs accumulated in inflamed tissues and ameliorated DSS-induced colitis via a local anti-inflammatory action.
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Affiliation(s)
- Fumio Tanaka
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
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Hayashi Y, Tsuji S, Tsujii M, Nishida T, Ishii S, Iijima H, Nakamura T, Eguchi H, Miyoshi E, Hayashi N, Kawano S. Topical implantation of mesenchymal stem cells has beneficial effects on healing of experimental colitis in rats. J Pharmacol Exp Ther 2008; 326:523-531. [PMID: 18448866 DOI: 10.1124/jpet.108.137083] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2025] Open
Abstract
Mesenchymal stem cells (MSCs) are attractive cell sources in regenerative medicine. We examined the effects of topical MSCs implantation on an experimental model of inflammatory bowel disease. Putative MSCs, isolated from bone marrow aspirates of male rats by dish adherence and expanded in vitro, were characterized by flow cytometry, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and differentiation assays. Experimental colitis was induced by intraluminal instillation of 2,4,6-trinitrobonzene sulfonic acid (TNBS) in the colons of male rats. The putative MSCs and unselected fresh bone marrow cells were injected into the colonic submucosa surrounding the area exposed to TNBS. The healing process of the injury was examined macroscopically and immunohistologically. Multipotent MSCs positive for CD29 and CD90, and negative for CD31 and CD34, were implanted into colon tissue surrounding the lesion; a majority of the engrafted cells were positive for vimentin. The implantation significantly accelerated healing of the damaged mucosa compared with vehicle-injected controls. The MSCs expressed vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-beta1 in vitro and after the implantation. In conclusion, we found that MSCs were successfully topically implanted in the colon and that they were associated with accelerated healing of TNBS-induced colitis. The beneficial effects of the MSCs might be mediated, at least in part, by their ability to differentiate into colonic interstitial cells and by their ability to provide VEGF and TGF-beta1 to the injured area.
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Affiliation(s)
- Yujiro Hayashi
- Department of Clinical Laboratory Science, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
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Stem cells as potential novel therapeutic strategy for inflammatory bowel disease. J Crohns Colitis 2008; 2:99-106. [PMID: 21172199 DOI: 10.1016/j.crohns.2007.12.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2007] [Accepted: 12/21/2007] [Indexed: 02/08/2023]
Abstract
Hematopoietic stem cell transplantation and mesenchymal stromal cell therapy are currently under investigation as novel therapies for inflammatory bowel diseases. Hematopoietic stem cells (HSC) are thought to repopulate the immune system and reset the immunological response to luminal antigens. Mesenchymal stromal cells (MSC) are cells that have the capacity to differentiate into wide variety of distinct cell lineages and suppress immune responses in vitro and in vivo. Recent results from animal models and early human experience in graft-versus-host disease but also Crohn's Disease suggest that ex vivo expanded MSCs may have clinically useful immunomodulatory effects.
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Hayashi Y, Tsuji S, Tsujii M, Nishida T, Ishii S, Iijima H, Nakamura T, Eguchi H, Miyoshi E, Hayashi N, Kawano S. Topical transplantation of mesenchymal stem cells accelerates gastric ulcer healing in rats. Am J Physiol Gastrointest Liver Physiol 2008; 294:G778-G786. [PMID: 18202110 DOI: 10.1152/ajpgi.00468.2007] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Mesenchymal stem cells (MSCs), a subpopulation of adult somatic stem cells, are an attractive stem cell source in regenerative medicine because of their multipotentiality. We examined the effects of MSC transplantation on gastric ulcer healing. Putative MSCs, isolated from bone marrow aspirates of male rats by dish adherence and expanded in culture, were characterized by flow cytometry and reverse transcription-polymerase chain reaction. Gastric ulcers were induced by serosal application of acetic acid on the anterior wall of the stomach in female rats. Either MSCs (labeled with PKH67; 1x10(7) cells) or vehicle was injected into the gastric wall surrounding the ulcer. The healing process of the ulcer and the influence of anti-vascular endothelial growth factor (VEGF) antibody were examined. CD29-positive, CD90-positive, CD34-negative, and CD45-negative MSCs expressed mRNAs for VEGF and hepatocyte growth factor (HGF). The MSCs were transplantable to the gastric tissue surrounding the ulcer, where a majority of the engrafted cells were positive for vimentin. The transplantation significantly accelerated gastric ulcer healing compared with controls. The engrafted MSCs also expressed VEGF and HGF. Administration of anti-VEGF neutralizing antibody dose dependently reduced the MSC-induced promotion of ulcer healing. In conclusion, MSC transplantation accelerated gastric ulcer healing, possibly through the induction of angiogenesis in the gastric mucosa via the secretion of VEGF. The beneficial effects of MSCs might be mediated not only by their differentiation into gastric interstitial cells, but also by their ability to supply angiogenic factors.
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Affiliation(s)
- Yujiro Hayashi
- Department of Clinical Laboratory Science, Osaka University Graduate School of Medicine, Suita, Osaka, 565-0871, Japan
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Nishida T, Tsuji S, Tsujii M, Ishii S, Yoshio T, Shinzaki S, Egawa S, Irie T, Kakiuchi Y, Yasumaru M, Iijima H, Tsutsui S, Kawano S, Hayashi N. Cultured bone marrow cell local implantation accelerates healing of ulcers in mice. J Gastroenterol 2008; 43:124-135. [PMID: 18306986 DOI: 10.1007/s00535-007-2137-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2007] [Accepted: 10/24/2007] [Indexed: 02/04/2023]
Abstract
BACKGROUND The therapeutic potential of bone marrow (BM)-derived cells in ulcers is not known. This study aimed to clarify (1) cell types that are derived from the BM which infiltrate ulcers; (2) whether BM-derived cells or gastric myofibroblasts can be used for cell transplantation to treat ulcers; and (3) the phenotypes of such transplantable cells. METHODS (1) Wild-type mice were transplanted with BM cells of green fluorescent protein (GFP)-transgenic mice. Acetic acid-induced gastric ulcers were produced in mice after BM transplantation. (2) BM cells and gastric myofibroblasts were isolated from GFP-transgenic mice. Bone marrow cells attached to plastic dishes were selected for expansion. Gastric ulcers were induced, and BM-derived cells, myofibroblasts, or phosphate-buffered saline were injected around ulcers. The ulcer healing process was examined macroscopically and histologically. (3) Expression of growth factors and cytokines in transplantable cells was examined by reverse transcriptase-polymerase chain reaction. RESULTS (1) GFP-positive cells with interstitial phenotypes were observed at the ulcerated area. (2) Ulcer healing was significantly promoted by the injection of BM-derived cells compared to controls on day 7, but not on day 3. The BM-derived cells were observed in the tissue surrounding the ulcer. However, myofibroblasts were not found. (3) The BM-derived cells expressed hepatocyte growth factor, transforming growth factor-beta(1), and other stromal factors before transplantation, and had mesenchymal phenotypes after transplantation. CONCLUSIONS BM-derived cells are involved in the ulcer healing. BM-derived cells, but not myofibroblasts, are locally implantable to ulcers. Thus, BM-derived cells can be transplanted to accelerate ulcer healing.
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Affiliation(s)
- Tsutomu Nishida
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Clinical Research Building (K1), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan
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Thapar N, Lindley KJ, Kiparissi F, Elawad MA, Ashworth M, Veys P, Gaspar HB, Hill SM, Milla PJ, Shah N. Treatment of intractable ulcerating enterocolitis of infancy by allogeneic bone marrow transplantation. Clin Gastroenterol Hepatol 2008; 6:248-50. [PMID: 18187369 DOI: 10.1016/j.cgh.2007.11.019] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Intractable ulcerating enterocolitis of infancy (IE) is an uncommon, autosomal-recessive, and devastating inflammatory bowel disorder that arises as a consequence of a poorly defined underlying immunologic disorder. Infants with IE suffer from recurrent severe oro-anal disease and an enterocolitis that is unresponsive to conventional immunosuppressive therapy and requires early pancolectomy to control the severity of the disease. Despite such aggressive treatment these individuals remain at high risk of Epstein-Barr virus-driven lymphomatous proliferations, including non-Hodgkin's lymphoma. The underlying genetic basis for this disease remains undefined. This report aims to describe the use of bone marrow transplantation as a treatment for this condition. METHODS This was a case series report. RESULTS We describe the successful treatment of IE by allogeneic bone marrow transplantation in 2 brothers, now aged 7 and 11 years, one of whom had developed an Epstein-Barr virus-related monomorphous B-lymphocyte lymphoproliferative disorder. This treatment has resulted in prolonged clinical remission in both boys and abrogated the need for aggressive immunosuppression. CONCLUSIONS Bone marrow transplantation can be used for the treatment of intractable ulcerating enterocolitis of infancy, which may support a role in other intractable inflammatory bowel conditions in the pediatric population.
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Affiliation(s)
- Nikhil Thapar
- Gastroenterology Unit, Great Ormond Street Hospital, London, United Kingdom.
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Păunescu V, Deak E, Herman D, Siska IR, Tănasie G, Bunu C, Anghel S, Tatu CA, Oprea TI, Henschler R, Rüster B, Bistrian R, Seifried E. In vitro differentiation of human mesenchymal stem cells to epithelial lineage. J Cell Mol Med 2007; 11:502-8. [PMID: 17635641 PMCID: PMC3922356 DOI: 10.1111/j.1582-4934.2007.00041.x] [Citation(s) in RCA: 120] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Our study examined whether human bone marrow-derived MSCs are able to differentiate, in vitro, into functional epithelial-like cells. MSCs were isolated from the sternum of 8 patients with different hematological disorders. The surface phenotype of these cells was characterized.To induce epithelial differentiation, MSCs were cultured using Epidermal Growth Factor, Keratinocyte Growth Factor, Hepatocyte Growth Factor and Insulin-like growth Factor-II. Differentiated cells were further characterized both morphologically and functionally by their capacity to express markers with specificity for epithelial lineage. The expression of cytokeratin 19 was assessed by immunocytochemistry, and cytokeratin 18 was evaluated by quantitative RT-PCR (Taq-man). The data demonstrate that human MSCs isolated from human bone marrow can differentiate into epithelial-like cells and may thus serve as a cell source for tissue engineering and cell therapy of epithelial tissue.
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Affiliation(s)
- Virgil Păunescu
- Department of Physiology and Immunology, University of Medicine and Pharmacy Victor Babes Timisoara, Romania.
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Hayashi Y, Tsuji S, Tsujii M, Nishida T, Ishii S, Nakamura T, Eguchi H, Kawano S. The transdifferentiation of bone-marrow-derived cells in colonic mucosal regeneration after dextran-sulfate-sodium-induced colitis in mice. Pharmacology 2007; 80:193-199. [PMID: 17587885 DOI: 10.1159/000104148] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2006] [Accepted: 03/28/2007] [Indexed: 12/14/2022]
Abstract
Bone-marrow-derived cells (BMDCs) transdifferentiate into various types of gastrointestinal cells. The precise transdifferentiation of BMDCs in gut regeneration, however, is controversial. In this study, we examined the transdifferentiation of BMDCs in the regeneration of damaged colonic epithelia. Lethally irradiated wild-type female mice (C57BL/6) were rescued by bone marrow transplantation from male green fluorescent protein transgenic mouse donors. Chronic colitis was induced by administering 3% dextran sulfate sodium (DSS) in the drinking water for 5 days on day 28 after the bone marrow transplantation. The mice were killed on day 25 after DSS administration. BMDC phenotypes were examined by confocal microscopy and fluorescence immunohistochemistry. BMDCs were frequently observed in the vimentin-positive colonic interstitial cells, which also expressed alpha-smooth muscle actin and had a spindle-like morphology, but did not express leukocyte common antigen. Green-fluorescent-protein-positive cells were rarely or less frequently found in Ki-67-positive proliferating cells, cytokeratin-positive epithelial cells, or CD31-positive endothelial cells. BMDCs frequently transdifferentiated into subepithelial myofibroblasts and fibroblasts, and often continued to reside in the colonic subepithelia after the experimental colitis had healed. In conclusion, our data indicate the fate of BMDCs, which might be involved in the healing process of the colon after DSS-induced colitis. Our data show that BMDCs contribute to colonic interstitial cells after the colitis has healed. Understanding the fate of BMDCs may be important for stem cell therapy by BMDCs.
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Affiliation(s)
- Yujiro Hayashi
- Department of Clinical Laboratory Science, Osaka University Graduate School of Medicine, Suita, Japan.
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Brittan M, Alison MR, Schier S, Wright NA. Bone marrow stem cell-mediated regeneration in IBD: where do we go from here? Gastroenterology 2007; 132:1171-3. [PMID: 17383436 DOI: 10.1053/j.gastro.2007.01.064] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Khalil PN, Weiler V, Nelson PJ, Khalil MN, Moosmann S, Mutschler WE, Siebeck M, Huss R. Nonmyeloablative stem cell therapy enhances microcirculation and tissue regeneration in murine inflammatory bowel disease. Gastroenterology 2007; 132:944-54. [PMID: 17383423 DOI: 10.1053/j.gastro.2006.12.029] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2006] [Accepted: 11/16/2006] [Indexed: 01/16/2023]
Abstract
BACKGROUND AND AIMS Reduced microcirculation has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Stem cells or endothelial progenitor cells are thought to contribute to tissue regeneration through neoangiogenesis or vasculogenesis in ischemia- or inflammatory-related diseases. We therefore hypothesized that adult stem cells facilitate epithelial repair in IBD. METHODS Moderate-severe colitis in mice was induced by dextran sulfate sodium (DSS) and 2.0 x 10(6) immortalized CD34(-) stem cells infused twice via the tail vein during an observation period of 35 days in a nonmyeloablative setting. RESULTS Here, we demonstrate that adult stem cells home to the damaged digestive tract in the large intestine and facilitate mucosal repair in moderate-severe colitis. Nonmyeloablative stem cell therapy resulted in increased survival in severe colitis (P < .0001). Moreover, clinical activity and histologic evaluation of the colitis severity score were reduced significantly in moderate (P = .0003 or P = .03) and severe (P < .0001 or P < .03) colitis after 35 days, in addition to the DSS-induced shortening of colon length (P = .002 and P < .0002). Genetically marked stem cells were detected predominantly in the submucosa of the damaged colon epithelium. Epithelial repair in experimental IBD was mediated either by induction of improved vasculogenesis or by the differentiation of the transplanted stem cells into endothelial cells, as demonstrated by the promotion of Tie2 activity in the infused cells at the site of the damaged mucosa. CONCLUSIONS Our findings indicate that systemically administered adult stem cells respond to an adequate tissue lesion in murine IBD by enhancing microcirculation, resulting in accelerated tissue repair.
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Affiliation(s)
- Philipe N Khalil
- Department of Surgery, Klinikum Innenstadt, Ludwig-Maximilians-Universität of München, Munich, Germany.
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Leung Y, Geddes M, Storek J, Panaccione R, Beck PL. Hematopoietic cell transplantation for Crohn’s disease; is it time? World J Gastroenterol 2006; 12:6665-73. [PMID: 17075981 PMCID: PMC4125673 DOI: 10.3748/wjg.v12.i41.6665] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To review all studies in the literature that have assessed Hematopoietic cell transplantation (HCT) and Crohn’s disease (CD) with the ultimate aims of determining if this is a viable treatment option for those with CD. A secondary aim was to review the above literature and determine if the studies shed further light on the mechanisms involved in the pathogenesis of CD.
METHODS: An extensive Medline search was performed on all articles from 1970 to 2005 using the keywords; bone marrow transplant, stem cell, hematopoietic cell, Crohn’s disease and inflammatory bowel disease.
RESULTS: We identified one case in which a patient developed CD following an allogeneic HCT from a sibling suffering with CD. Evidence for transfer of the genetic predisposition to develop CD was also identified with report of a patient that developed severe CD following an allogeneic HCT. Following HCT it was found that the donor (that had no signs or symptoms of CD) and the recipient had several haplotype mismatches in HLA class III genes in the IBD3 locus including a polymorphism of NOD2/CARD15 that has been associated with CD. Thirty three published cases of patients with CD who underwent either autologous or allogeneic HCT were identified. At the time of publication 29 of these 33 patients were considered to be in remission. The median follow-up time was seven years, and twenty months for allogeneic and autologous HCT respectively. For patients who underwent HCT primarily for treatment of their CD there have been no mortalities related to transplant complications.
CONCLUSION: Overall these preliminary data suggest that both allogeneic and autologous HCT may be effective in inducing remission in refractory CD. This supports the hypothesis that the hemolymphatic cells play a key role in CD and that resetting of the immune system may be a critical approach in the management or cure of CD.
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Affiliation(s)
- Y Leung
- Department of Medicine, University of Calgary, Health Sciences Center, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada
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Bamba S, Lee CY, Brittan M, Preston SL, Direkze NC, Poulsom R, Alison MR, Wright NA, Otto WR. Bone marrow transplantation ameliorates pathology in interleukin-10 knockout colitic mice. J Pathol 2006; 209:265-73. [PMID: 16550633 DOI: 10.1002/path.1967] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The authors have previously reported the derivation of colonic subepithelial myofibroblasts (SEMFs) in both humans and mice from bone marrow (BM). In the pathogenesis of inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis, colonic SEMFs mediate several types of inflammatory response. In the present study, interleukin (IL)-10-/- mice were used as a model of IBD to investigate the involvement of BM-derived cells in the inflamed mucosa. Male whole BM [either C57/BL10 (wild type: WT) or IL-10-/- donor mice] was used to perform bone marrow transplantation (BMT) into both WT and IL-10-/- female mice. Tissue samples were evaluated by immunohistochemistry for alpha-smooth muscle actin expression and by in situ hybridization using a Y-chromosome-specific probe to track the donor-derived colonic SEMFs. The mucosal expression of mRNA for pro-inflammatory cytokines was analysed by reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, mRNA expression of matrix metalloproteinase (MMP)-7 and osteopontin in the inflamed mucosa was assessed using in situ hybridization. Body weights and histological scores showed that IL-10-/- mice that received WT BM had an improved course of colitis, decreased mucosal pro-inflammatory mRNA expression, and up to 30% of their SEMFs were of BM origin. Conversely, IL-10-/- mice receiving IL-10-/- BM progressed to extensive colitis, and Y probe analysis revealed that up to 45% of colonic SEMFs were of BM origin. WT mice receiving IL-10-/- or WT BM had no signs of colonic inflammation. The expression of MMP-7 and osteopontin was up-regulated in the inflamed mucosa. In conclusion, IL-10-/- mice displayed ameliorated disease activity after WT BMT, whilst colitis was not induced in WT mice by IL-10-/- BMT. The contribution of BM-derived cells to colonic SEMFs was significantly increased in the inflamed mucosa compared with non-inflamed mucosa.
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Affiliation(s)
- S Bamba
- Histopathology Unit, London Research Institute, Cancer Research UK, London WC2A 3PX, UK.
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Coyne TM, Marcus AJ, Woodbury D, Black IB. Marrow stromal cells transplanted to the adult brain are rejected by an inflammatory response and transfer donor labels to host neurons and glia. Stem Cells 2006; 24:2483-92. [PMID: 16873764 DOI: 10.1634/stemcells.2006-0174] [Citation(s) in RCA: 188] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Abstract The remarkable plasticity of marrow stromal cells (MSCs) after transplantation to models of neurological disease and injury has been described. In this report, we investigated the plasticity and long-term survival of MSCs transplanted into the normal brain. MSCs were isolated from green fluorescent protein (GFP) transgenic rats and double-labeled with 5-bromo-2-deoxyuridine (BrdU) and bis benzamide (BBZ) prior to transplantation into the adult hippocampus or striatum. Surgery elicited an immediate inflammatory response. MSC grafts were massively infiltrated by ED1-positive microglia/macrophages and surrounded by a marked astrogliosis. By 14 days, graft volume had retracted and GFP immunoreactivity was absent, indicating complete donor rejection. Consequently, MSCs did not exhibit plasticity formerly identified in other studies. However, BrdU- and BBZ-labeled cells were detected up to 12 weeks. Control transplants of nonviable MSCs demonstrated the transfer of donor labels to host cells. Unexpectedly, BrdU labeling was colocalized to host phagocytes, astrocytes, and neurons in both regions. Our results indicate that MSCs transplanted to the intact adult brain are rejected by an inflammatory response. Moreover, use of the traditional cell labels BrdU and BBZ may provide a misleading index of donor survival and differentiation after transplantation.
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Affiliation(s)
- Thomas M Coyne
- The Ira B. Black Center for Stem Cell Rersearch and Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854-5635, USA.
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