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Zhu F, Ji L, Dai K, Deng S, Wang J, Liu C. In situ licensing of mesenchymal stem cell immunomodulatory function via BMP-2 induced developmental process. Proc Natl Acad Sci U S A 2024; 121:e2410579121. [PMID: 39565311 PMCID: PMC11621467 DOI: 10.1073/pnas.2410579121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 10/21/2024] [Indexed: 11/21/2024] Open
Abstract
The immunomodulatory function of mesenchymal stem cells (MSCs) is plastic and susceptible to resident microenvironment in vivo or inflammatory factors in vitro. We propose a unique method to enhance the immunoregulatory functions of mesenchymal stem cells (MSCs) through an artificially controllable in vivo inflammatory microenvironment generated by biomaterials loaded with BMP-2 that induce bone development. MSCs activated through this method effectively induce M1 macrophage polarization toward the M2 phenotype, promote differentiation of naïve T cells into regulatory T cells, and inhibit the proliferation of activated T cells via prostaglandin E2 (PGE2) secretion. This in vivo licensing not only preserves the immunogenicity of MSCs but also alters DNA methylation patterns, enabling MSCs to exhibit immunoregulatory effects with epigenetic memory. Validation in a mouse colitis model demonstrated their therapeutic efficacy and long-term viability. Furthermore, we found that the material composition influences the inflammatory response during development, with polysaccharide-based biomaterials proving advantageous over protein-based materials in establishing an inflammatory niche conducive to MSC activity. These findings underscore the potential of tissue engineering to create in vivo environments that license MSCs, offering a strategic avenue to enhance MSC-based therapies for addressing significant immune disorders.
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Affiliation(s)
- Fuwei Zhu
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai200237, People’s Republic of China
- School of Materials Science and Engineering, Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai200237, People’s Republic of China
| | - Luli Ji
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai200237, People’s Republic of China
- School of Materials Science and Engineering, Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai200237, People’s Republic of China
| | - Kai Dai
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai200237, People’s Republic of China
- School of Materials Science and Engineering, Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai200237, People’s Republic of China
| | - Shunshu Deng
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai200237, People’s Republic of China
- School of Materials Science and Engineering, Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai200237, People’s Republic of China
| | - Jing Wang
- The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai200237, People’s Republic of China
- School of Materials Science and Engineering, Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai200237, People’s Republic of China
- Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai200237, People’s Republic of China
| | - Changsheng Liu
- School of Materials Science and Engineering, Engineering Research Center for Biomedical Materials of the Ministry of Education, East China University of Science and Technology, Shanghai200237, People’s Republic of China
- Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai200237, People’s Republic of China
- School of Materials Science and Engineering, Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai200237, People’s Republic of China
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Zhu Y, Chen X, Yang X, El-Hashash A. Stem cells in lung repair and regeneration: Current applications and future promise. J Cell Physiol 2018; 233:6414-6424. [PMID: 29271480 DOI: 10.1002/jcp.26414] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 12/19/2017] [Indexed: 12/18/2022]
Abstract
Lung diseases are major cause of morbidity and mortality worldwide. The progress in regenerative medicine and stem cell research in the lung are currently a fast-growing research topic that can provide solutions to these major health problems. Under normal conditions, the rate of cellular proliferation is relatively low in the lung in vivo, compared to other major organ systems. Lung injury leads to the activation of stem/progenitor cell populations that re-enter the cell cycle. Yet, little is known about stem cells in the lung, despite common thoughts that these cells could play a critical role in the repair of lung injuries. Nor do we fully understand the cellular and architectural complexity of the respiratory tract, and the diverse stem/progenitor cells that are involved in the lung repair and regeneration. In this review, we discuss the conceptual framework of lung stem/progenitor cell biology, and describe lung diseases, in which stem cell manipulations may be physiologically significant. In addition, we highlight the challenges of lung stem cell-based therapy.
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Affiliation(s)
- Yuqing Zhu
- Centre of Stem cell and Regenerative Medicine, Schools of Medicine and Basic Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiao Chen
- Centre of Stem cell and Regenerative Medicine, Schools of Medicine and Basic Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xu Yang
- Section of Environmental Biomedicine, School of Life Science, Central China Normal University, Wuhan, Hubei, China
| | - Ahmed El-Hashash
- Centre of Stem cell and Regenerative Medicine, Schools of Medicine and Basic Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,University of Edinburgh-Zhejiang University Institute (UoE-ZJU Institute), Haining, Zhejiang, China.,Edinburgh Medical School, University of Edinburgh, Edinburgh, UK
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Naguib E, Kamel A, Fekry O, Abdelfattah G. Comparative study on the effect of low intensity laser and growth factors on stem cells used in experimentally-induced liver fibrosis in mice. Arab J Gastroenterol 2017. [PMID: 28625529 DOI: 10.1016/j.ajg.2017.05.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND STUDY AIMS The therapeutic effects of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) exposed to diode laser and/or hepatocyte growth factor (HGF) were compared in mice with experimental liver fibrosis induced by carbon tetra chloride (CCl4). MATERIAL AND METHODS Animal model of liver cirrhosis was induced by intraperitoneal injection of CCl4 in a dose of 0.4ml/kg, twice a week for 6weeks. UC-MSCs were obtained from normal full term placentas and were exposed to diode laser and/or HGF. Before treatment, UC-MSCs were labelled with red fluorescent PKH26. Fifty four male mice weighing 25-35g were randomly divided into four groups control, stem cells, CCl4, and treated groups. After the experimental period, body and liver weights were recorded, and the liver specimens were processed for histological examination using haematoxylin and eosin, Periodic Acid-Schiff (PAS), and Masson's Trichrome staining (MT). RESULTS Results showed that administration of UC-MSCs stimulated by diode laser and/or HGF improved body and liver weights, reduced vascular dilatation and congestion, reduced mononuclear cellular infiltration, reduced hepatocyte vacuolation, eosinophilia, and pyknosis. Furthermore, periportal fibrosis was minimized and PAS reaction was increased. These effects were maximum when UC-MSCs were exposed to both diode laser and HGF. CONCLUSION UC-MSCs stimulated by both diode laser and HGF proved to be an effective therapeutic option in experimental liver fibrosis induced by CCl4 in mice.
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Affiliation(s)
- Eman Naguib
- Department of Laser Sciences and Interactions, National Institute of Laser and Enhanced Sciences, Cairo University, Cairo, Egypt.
| | - Ashraf Kamel
- Department of Histology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Osama Fekry
- Department of Medical Laser Applications, National Institute of Laser and Enhanced Sciences, Cairo University, Cairo, Egypt
| | - Gamal Abdelfattah
- Department of Laser Sciences and Interactions, National Institute of Laser and Enhanced Sciences, Cairo University, Cairo, Egypt
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Lee PH, Tu CT, Hsiao CC, Tsai MS, Ho CM, Cheng NC, Hung TM, Shih DTB. Antifibrotic Activity of Human Placental Amnion Membrane-Derived CD34+ Mesenchymal Stem/Progenitor Cell Transplantation in Mice With Thioacetamide-Induced Liver Injury. Stem Cells Transl Med 2016; 5:1473-1484. [PMID: 27405780 DOI: 10.5966/sctm.2015-0343] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 04/18/2016] [Indexed: 12/31/2022] Open
Abstract
: Liver fibrosis represents the end stage of chronic liver inflammatory diseases and is defined by the abnormal accumulation of extracellular matrix in the liver. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension. Liver transplantation has been the most effective treatment for these diseases, but the procedure is limited by the shortage of suitable donors. Mesenchymal stromal cells (MSCs) have shown great potential in the treatment of chronic inflammatory diseases associated with fibrosis. This study aimed to evaluate the therapeutic effect of MSC-based cell transplantation as an alternative treatment for liver fibrosis. A CD34-positive subpopulation of human placental amnion membrane-derived stem/progenitor cells (CD34+ AMSPCs) was isolated through the depletion of CD34-negative stromal fibroblasts (CD34- AMSFCs) facilitated by CD34 fluorescence-activated cell sorting, enriched and expanded ex vivo. These cells express pluripotency markers and demonstrate multidirectional differentiation potentials. Comparative analysis was made between CD34+ AMSPCs and CD34- AMSFCs in terms of the expressions of stemness surface markers, embryonic surface antigens, and multilineage differentiation potentials. A mouse model of liver fibrosis was established by thioacetamide (TAA) administration. When injected into the spleen of TAA-injured mice, human placental amnion membrane-derived MSCs (hAM-MSCs) can engraft into the injury site, ameliorate liver fibrosis, and restore liver function, as shown by pathological and blood biochemical analysis and downregulated gene expressions associated with liver damage. CD34+ AMSPCs represent a more primitive subset of hAM-MSCs and could be a suitable candidate with a potentially better safety profile for cell-based therapy in treatment of liver diseases associated with fibrosis. SIGNIFICANCE In this study, a CD34+ subpopulation of stem/progenitor cells derived from neonatal placental amnion membrane, denoted as CD34+ AMSPCs, were identified, enriched, and characterized. These cells are highly proliferative, express mesenchymal stromal cells and pluripotent stem cell markers, and demonstrate multidirectional differentiation potentials, indicating their promising application in clinical regenerative therapies. CD34+ AMSPC transplantation ameliorated liver fibrosis in mice with drug-induced liver injury. These cells represent a potential therapeutic agent for treating liver diseases associated with fibrosis.
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Affiliation(s)
- Po-Huang Lee
- National Taiwan University Hospital, Taipei City, Taiwan, Republic of China
- E-Da Hospital/I-Shou University, Yan-Chau Shiang, Kaohsiung County, Taiwan, Republic of China
| | - Chi-Tang Tu
- National Taiwan University Hospital, Taipei City, Taiwan, Republic of China
| | - Chih-Chiang Hsiao
- Taipei Medical University Hospital, Taipei City, Taiwan, Republic of China
| | - Ming-Song Tsai
- Prenatal Diagnosis Center, Cathay General Hospital, Taipei City, Taiwan, Republic of China
| | - Cheng-Maw Ho
- National Taiwan University Hospital, Taipei City, Taiwan, Republic of China
| | - Nai-Chen Cheng
- National Taiwan University Hospital, Taipei City, Taiwan, Republic of China
| | - Tzu-Min Hung
- National Taiwan University Hospital, Taipei City, Taiwan, Republic of China
- E-Da Hospital/I-Shou University, Yan-Chau Shiang, Kaohsiung County, Taiwan, Republic of China
| | - Daniel Tzu-Bi Shih
- E-Da Hospital/I-Shou University, Yan-Chau Shiang, Kaohsiung County, Taiwan, Republic of China
- Taipei Medical University Hospital, Taipei City, Taiwan, Republic of China
- Innovation Incubation Center, National Taiwan University Hospital, Taipei City, Taiwan, Republic of China
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Cordeiro IR, Lopes DV, Abreu JG, Carneiro K, Rossi MID, Brito JM. Chick embryo xenograft model reveals a novel perineural niche for human adipose-derived stromal cells. Biol Open 2015; 4:1180-93. [PMID: 26319582 PMCID: PMC4582113 DOI: 10.1242/bio.010256] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Human adipose-derived stromal cells (hADSC) are a heterogeneous cell population that contains adult multipotent stem cells. Although it is well established that hADSC have skeletal potential in vivo in adult organisms, in vitro assays suggest further differentiation capacity, such as into glia. Thus, we propose that grafting hADSC into the embryo can provide them with a much more instructive microenvironment, allowing the human cells to adopt diverse fates or niches. Here, hADSC spheroids were grafted into either the presumptive presomitic mesoderm or the first branchial arch (BA1) regions of chick embryos. Cells were identified without previous manipulations via human-specific Alu probes, which allows efficient long-term tracing of heterogeneous primary cultures. When grafted into the trunk, in contrast to previous studies, hADSC were not found in chondrogenic or osteogenic territories up to E8. Surprisingly, 82.5% of the hADSC were associated with HNK1+ tissues, such as peripheral nerves. Human skin fibroblasts showed a smaller tropism for nerves. In line with other studies, hADSC also adopted perivascular locations. When grafted into the presumptive BA1, 74.6% of the cells were in the outflow tract, the final goal of cardiac neural crest cells, and were also associated with peripheral nerves. This is the first study showing that hADSC could adopt a perineural niche in vivo and were able to recognize cues for neural crest cell migration of the host. Therefore, we propose that xenografts of human cells into chick embryos can reveal novel behaviors of heterogeneous cell populations, such as response to migration cues.
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Affiliation(s)
- Ingrid R Cordeiro
- Morphological Sciences Program, Biomedical Sciences Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | - Daiana V Lopes
- Morphological Sciences Program, Biomedical Sciences Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | - José G Abreu
- Morphological Sciences Program, Biomedical Sciences Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | - Katia Carneiro
- Morphological Sciences Program, Biomedical Sciences Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | - Maria I D Rossi
- Morphological Sciences Program, Biomedical Sciences Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | - José M Brito
- Morphological Sciences Program, Biomedical Sciences Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
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Garg S, Wang W, Prabath BG, Boerma M, Wang J, Zhou D, Hauer-Jensen M. Bone marrow transplantation helps restore the intestinal mucosal barrier after total body irradiation in mice. Radiat Res 2014; 181:229-39. [PMID: 24568131 DOI: 10.1667/rr13548.1] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Bone marrow transplantation (BMT) substantially improves 10-day survival after total body irradiation (TBI), consistent with an effect on intestinal radiation death. Total body irradiation, in addition to injuring the intestinal epithelium, also perturbs the mucosal immune system, the largest immune system in the body. This study focused on how transplanted bone marrow cells (BMCs) help restore mucosal immune cell populations after sublethal TBI (8.0 Gy). We further evaluated whether transplanted BMCs: (a) home to sites of radiation injury using green fluorescent protein labeled bone marrow; and (b) contribute to restoring the mucosal barrier in vivo. As expected, BMT accelerated recovery of peripheral blood (PB) cells. In the intestine, BMT was associated with significant early recovery of mucosal granulocytes (P = 0.005). Bone marrow transplantation did not affect mucosal macrophages or lymphocyte populations at early time points, but enhanced the recovery of these cells from day 14 onward (P = 0.03). Bone marrow transplantation also attenuated radiation-induced increase of intestinal CXCL1 and restored IL-10 levels (P = 0.001). Most importantly, BMT inhibited the post-radiation increase in intestinal permeability after 10 Gy TBI (P = 0.02) and modulated the expression of tight junction proteins (P = 0.01-0.05). Green fluorescent protein-positive leukocytes were observed both in intestinal tissue and in PB. These findings strongly suggest that BMT, in addition to enhancing general hematopoietic and immune system recovery, helps restore the intestinal immune system and enhances intestinal mucosal barrier function. These findings may be important in the development and understanding of strategies to alleviate or treat intestinal radiation toxicity.
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Affiliation(s)
- Sarita Garg
- a Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Tomida M, Tsujigiwa H, Nakano K, Muraoka R, Nakamura T, Okafuji N, Nagatsuka H, Kawakami T. Promotion of transplanted bone marrow-derived cell migration into the periodontal tissues due to orthodontic mechanical stress. Int J Med Sci 2013; 10:1321-6. [PMID: 23983592 PMCID: PMC3753415 DOI: 10.7150/ijms.6631] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 07/22/2013] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND Bone marrow-derived cells (BMCs) have abilities of cell migration and differentiation into tissues/organs in the body and related with the differentiation of teeth or periodontal tissue including fibroblasts. Then, we examined the effect of orthodontic mechanical stress to the transplanted BMC migration into periodontal tissues using BMC transplantation model. MATERIAL AND METHOD BMC from green fluorescence protein (GFP) transgenic mice were transplanted into 8-week-old female C57BL/6 immunocompromised recipient mice, which had undergone 10 Gy of lethal whole-body-irradiation. Five mice as experimental group were received orthodontic mechanical stress using separator between first molar (M1) and second molar (M2) 1 time per week for 5 weeks and 5 mice as control group were not received mechanical stress. The maxilla with M1 and M2 was removed and was immunohistochemically analyzed using a Dako Envision + Kit-K4006 and a primary anti-GFP-polyclonal rabbit antibody. Immunohistochemically stained was defined as positive area and the pixel number of positive area in the periodontal tissue was compared with the previously calculated total pixel number of the periodontal tissue. RESULTS The immunohistochemistry revealed that GFP positive cells were detected in the periodontal tissues, both in the experimental and control specimens. The ratio of pixel number in the examination group showed 5.77 ± 3.24 % (mean ± SD); and that in the control group, 0.71 ± 0.45 % (mean ± SD). The examination group was significantly greater than that of control group (Mann-Whitney U test: p<0.001). CONCLUSION These results suggest that orthodontic mechanical stress accelerates transplanted BMC migration into periodontal tissues.
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Affiliation(s)
- Mihoko Tomida
- Department of Oral Physiology, Matsumoto Dental University School of Dentistry, Shiojiri, Japan
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Ghasemzadeh-Hasankolaei M, Eslaminejad M, Batavani R, Sedighi-Gilani M. Comparison of the efficacy of three concentrations of retinoic acid for transdifferentiation induction in sheep marrow-derived mesenchymal stem cells into male germ cells. Andrologia 2012; 46:24-35. [DOI: 10.1111/and.12037] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/11/2012] [Indexed: 12/13/2022] Open
Affiliation(s)
| | - M.B. Eslaminejad
- Department of Stem Cells and Developmental Biology; Cell Science Research Center; Royan Institute for Stem Cell Biology and Technology; ACECR; Tehran Iran
| | - R. Batavani
- Department of Clinical Sciences; Faculty of Veterinary Medicine; Urmia University; Urmia Iran
| | - M. Sedighi-Gilani
- Department of Andrology; Reproductive Biomedicine Research Center; Royan Institute for Stem Cell Biology and Technology; ACECR; Tehran Iran
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Ding G, Shao J, Ding Q, Fang Z, Wu Z, Xu J, Gao P. Comparison of the characteristics of mesenchymal stem cells obtained from prostate tumors and from bone marrow cultured in conditioned medium. Exp Ther Med 2012; 4:711-715. [PMID: 23170131 PMCID: PMC3501413 DOI: 10.3892/etm.2012.642] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Accepted: 05/31/2012] [Indexed: 01/01/2023] Open
Abstract
Prostate cancer (PCa) is the most common type of cancer worldwide. Mesenchymal stem cells (MSCs) can also be utilized as ‘tumor stromal cells’, which are associated with invasive and metastatic malignant tumor cells. Our study aimed to investigate MSCs in prostate tumors and normal MSCs and evaluate their differential characteristics. Normal MSCs (BMMSCs) were isolated from the femur and tibia of normal mice; prostate tumor MSCs (PCa-MSCs) were obtained from prostate tumors implanted in mice. These two types of MSCs were induced to differentiate into adipocytes, bone cells and chondrocytes. Growth curves were used to analyze the growth ability of PCa-MSCs and BMMSCs. Tritium-labeled thymidine (3H-TdR) was used to evaluate cell proliferation of RM-1 stimulated by MSCs. The time taken for PCa-MSCs to reach 90% confluence was markedly shorter than that of BMMSCs (8–10 vs. 12–14 days). The differentiation ability of PCa-MSCs was similar to that described in previous reports. The growth ability of PCa-MSCs was significantly higher than that of BMMSCs. The proliferative activity of PCa-MSCs was also higher than that of BMMSCs. Our data showed that PCa-MSCs exhibit identical characteristics when compared with those of MSCs. Additionally, their proliferative activity and growth ability were significantly higher when compared with these values in BMMSCs, which appear to have an intrinsic, cell-specific capacity to localize to PCa. The possible role of PCa-MSCs in the process of PCa development requires further clarification.
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Affiliation(s)
- Guanxiong Ding
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, P.R. China
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Nakamura T, Torimura T, Iwamoto H, Masuda H, Naitou M, Koga H, Abe M, Hashimoto O, Tsutsumi V, Ueno T, Sata M. Prevention of liver fibrosis and liver reconstitution of DMN-treated rat liver by transplanted EPCs. Eur J Clin Invest 2012; 42:717-28. [PMID: 22224757 DOI: 10.1111/j.1365-2362.2011.02637.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Using the dimethylnitrosamine (DMN) rat model of induced fibrosis, we investigated whether transfer of in vitro-expanded endothelial progenitor cells (EPCs) could reconstitute liver tissue and protect against liver fibrosis. MATERIALS AND METHODS Low-density, adherent, rat bone marrow-derived mononuclear cells were cultured for one week in medium supporting the growth of chemokine (C-X-C motif) receptor 4 (CXCR4)-positive EPCs that were used for transplantation. Test rats were treated with weekly intraperitoneal injections of DMN over a period of 4 weeks. During that period, the rats were also transplanted weekly with in vivo-expanded EPCs. RESULTS Transplanted CXCR4-positive expanded EPCs entered around the portal tracts, fibrous septa and hepatic sinusoids, locations at which stromal cell-derived factor 1 (SDF-1), a ligand attracting CXCR4-positive cells, was expressed nearby. In EPC-transplanted rats, we observed suppression of liver fibrogenesis, reduced deposition of type I collagen and fibronectin, fewer α-smooth muscle actin-positive cells and lower expression of transforming growth factor (TGF)-β. The expression of growth factors promoting hepatic regeneration (hepatocyte growth factor, transforming growth factor-α (TGF-α), epidermal growth factor and vascular endothelial growth factor) was significantly increased in EPC-transplanted rats, resulting in hepatocyte proliferation. Immunohistochemical analyses of eNOS and isolectin B4 demonstrated that the livers of EPC-transplanted animals had markedly increased vascular density, suggesting reconstitution of sinusoidal blood vessels with endothelium. Liver function tests of transaminase, total bilirubin, total protein and albumin demonstrated that normal levels were maintained in EPC-transplanted rats. CONCLUSIONS EPC transplantation effectively promotes the remodelling of tissues damaged by liver fibrosis; it can also reconstitute sinusoids in chronic liver injury.
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Affiliation(s)
- Toru Nakamura
- Division of Gastroenterology, Department of Medicine, University School of Medicine Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan.
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Abstract
PURPOSE Mesenchymal stem cells (MSCs) are multipotent and give rise to distinctly differentiated cells from all three germ layers. Neuronal differentiation of MSC has great potential for cellular therapy. We examined whether the cluster of mechanically made, not neurosphere, could be differentiated into neuron-like cells by growth factors, such as epidermal growth factor (EGF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF). MATERIALS AND METHODS BMSCs grown confluent were mechanically separated with cell scrapers and masses of separated cells were cultured to form cluster BMSCs. As described here cluster of BMSCs were differentiated into neuron-like cells by EGF, HGF, and VEGF. Differentiated cells were analyzed by means of phase-contrast inverted microscopy, reverse transcriptase-polymerase chain reaction (RT-PCR), immunofluorescence, and immunocytochemistry to identify the expression of neural specific markers. RESULTS For the group with growth factors, the shapes of neuron-like cells was observable a week later, and two weeks later, most cells were similar in shape to neuron-like cells. Particularly, in the group with chemical addition, various shapes of filament structures were seen among the cells. These culture conditions induced MSCs to exhibit a neural cell phenotype, expressing several neuro-glial specific markers. CONCLUSION bone marrow-derived mesenchymal stem cells (BMSCs) could be easily induced to form clusters using mechanical scraping, not neurospheres, which in turn could differentiate further into neuron-like cells and might open an attractive possibility for clinical cell therapy for neurodegenerative diseases. In the future, we consider that neuron-like cells differentiated from clusters of BMSCs are needed to be compared and analyzed on a physiological and molecular biological level with preexisting neuronal cells, and studies on the possibility of their transplantation and differentiation capability in animal models are further required.
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Affiliation(s)
- Keum Seok Bae
- Department Surgery, Yonsei University Wonju College of Medicine, Wonju 220-701, Korea.
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Mahdipour E, Mace KA. Hox transcription factor regulation of adult bone-marrow-derived cell behaviour during tissue repair and regeneration. Expert Opin Biol Ther 2011; 11:1079-90. [PMID: 21513461 DOI: 10.1517/14712598.2011.579096] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Bone marrow offers a valuable source of stem/progenitor cells that contribute to the repair of injured tissues. Failure in the function of these cells results in delayed or reduced tissue repair. Identification of factors that can correct these defects is critical to treating the underlying dysfunction. Notably, homeobox (Hox) transcription factors have been identified as having significant effects on BMDC behaviour, including differentiation, migration and adhesion in injured tissue, and may provide a basis for future therapies. AREAS COVERED Hox protein regulation of bone-marrow-derived cell (BMDC) differentiation, factors that influence BMDC behaviour in response to injury, the effects of the diabetic environment on BMDCs, methods that can be used to reprogramme BMDCs, and the use of Hox transcription factors to correct BMDC behaviour. EXPERT OPINION Hox gene therapy has been successfully employed to change cell behaviour using ex vivo 'reprogramming' strategies overexpressing selected Hox genes in BMDCs to direct the fate of these cells to the desired cell type, promoting tissue repair.
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Affiliation(s)
- Elahe Mahdipour
- University of Manchester, Healing Foundation Centre, Faculty of Life Sciences, Oxford Road, Manchester M13 9PT, UK
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Lee MJ, Jung J, Na KH, Moon JS, Lee HJ, Kim JH, Kim GI, Kwon SW, Hwang SG, Kim GJ. Anti-fibrotic effect of chorionic plate-derived mesenchymal stem cells isolated from human placenta in a rat model of CCl(4)-injured liver: potential application to the treatment of hepatic diseases. J Cell Biochem 2011; 111:1453-63. [PMID: 20830742 DOI: 10.1002/jcb.22873] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Translational studies have explored the therapeutic effects of stem cells, raising hopes for the treatment of numerous diseases. Here, we evaluated the therapeutic effect of chorionic plate-derived mesenchymal stem cells (CP-MSCs) isolated from human placenta and transplanted into rats with carbon tetrachloride (CCl(4))-injured livers. CP-MSCs were analyzed for hepatocyte-specific gene expression, indocyanine green (ICG) uptake, glycogen storage, and urea production following hepatogenic differentiation. PKH26-labeled CP-MSCs were directly transplanted into the livers of rats that had been exposed to CCl(4) (1.6 g/kg, twice per week for 9 weeks). Blood and liver tissue were analyzed at 1, 2, and 3 weeks post-transplantation. The expression of type I collagen (Col I) and matrix metalloproteinases (MMPs) was analyzed in rat T-HSC/Cl-6 hepatic stellate cells co-cultured with CP-MSCs following exposure to TGF-β. The expression levels of α-smooth muscle actin (α-SMA) and Col I were lower in transplanted (TP) rats than in non-transplanted (Non-TP) animals (P < 0.05), whereas the expression levels of albumin and MMP-9 were increased. TP rats exhibited significantly higher uptake/excretion of ICG than non-TP rats (P < 0.005). In addition, collagen synthesis in T-HSC/Cl-6 cells exposed to TGF-β was decreased by co-culture with CP-MSCs, which triggered the activation of MMP-2 and MMP-9. These results contribute to our understanding of the potential pathophysiological roles of CP-MSCs, including anti-fibrotic effects in liver disease, and provide a foundation for the development of new cell therapy-based strategies for the treatment of difficult-to-treat liver diseases.
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Affiliation(s)
- Min-Jae Lee
- School of Veterinary Medicine, Kangwon National University, Chuncheon, Kangwon-do, Republic of Korea
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Tsujigiwa H, Katase N, Sathi GA, Buery RR, Hirata Y, Kubota M, Nakano K, Kawakami T, Nagatsuka H. Transplanted Bone Marrow derived Cells Differentiated toTooth, Bone and Connective Tissues in Mice. J HARD TISSUE BIOL 2011. [DOI: 10.2485/jhtb.20.147] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
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15
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Hoxa3 promotes the differentiation of hematopoietic progenitor cells into proangiogenic Gr-1+CD11b+ myeloid cells. Blood 2010; 117:815-26. [PMID: 20974673 DOI: 10.1182/blood-2009-12-259549] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Injury induces the recruitment of bone marrow-derived cells (BMDCs) that contribute to the repair and regeneration process. The behavior of BMDCs in injured tissue has a profound effect on repair, but the regulation of BMDC behavior is poorly understood. Aberrant recruitment/retention of these cells in wounds of diabetic patients and animal models is associated with chronic inflammation and impaired healing. BMD Gr-1(+)CD11b(+) cells function as immune suppressor cells and contribute significantly to tumor-induced neovascularization. Here we report that Gr-1(+)CD11b(+) cells also contribute to injury-induced neovascularization, but show altered recruitment/retention kinetics in the diabetic environment. Moreover, diabetic-derived Gr-1(+)CD11b(+) cells fail to stimulate neovascularization in vivo and have aberrant proliferative, chemotaxis, adhesion, and differentiation potential. Previously we demonstrated that gene transfer of HOXA3 to wounds of diabetic mice is taken up by and expressed by recruited BMDCs. This is associated with a suppressed inflammatory response, enhanced neovascularization, and accelerated wound healing. Here we show that sustained expression of Hoxa3 in diabetic-derived BMD Gr-1(+)CD11b(+) cells reverses their diabetic phenotype. These findings demonstrate that manipulation of adult stem/progenitor cells ex vivo could be used as a potential therapy in patients with impaired wound healing.
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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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Filip S, Mokry J, Horacek J, English D. Stem Cells and the Phenomena of Plasticity and Diversity: A Limiting Property of Carcinogenesis. Stem Cells Dev 2008; 17:1031-8. [DOI: 10.1089/scd.2007.0234] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Affiliation(s)
- Stanislav Filip
- Department of Oncology and Radiotherapy, Charles University in Prague, Faculty of Medicine and Teaching Hospital, Hradec Králové, Czech Republic
| | - Jaroslav Mokry
- Department of Histology and Embryology, Charles University in Prague, Faculty of Medicine and Teaching Hospital, Hradec Králové, Czech Republic
| | - Jiri Horacek
- Department of Medicine, Charles University in Prague, Faculty of Medicine and Teaching Hospital, Hradec Králové, Czech Republic
| | - Denis English
- Department of Neurosurgery, University of South Florida, College of Medicine, Tampa, Florida
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Li JT, Liao ZX, Ping J, Xu D, Wang H. Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies. J Gastroenterol 2008; 43:419-28. [PMID: 18600385 DOI: 10.1007/s00535-008-2180-y] [Citation(s) in RCA: 120] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2007] [Accepted: 02/25/2008] [Indexed: 02/06/2023]
Abstract
Activation of hepatic stellate cells (HSCs) is the dominant event in liver fibrosis. The early events in the organization of HSC activation have been termed initiation. Initiation encompasses rapid changes in gene expression and phenotype that render the cells responsive to cytokines and other local stimuli. Cellular responses following initiation are termed perpetuation, which encompasses those cellular events that amplify the activated phenotype through enhanced growth factor expression and responsiveness. Multiple cells and cytokines play a part in the regulation of HSC activation. HSC activation consists of discrete phenotype responses, mainly proliferation, contractility, fibrogenesis, matrix degradation, chemotaxis and retinoid loss. Currently, antifibrotic therapeutic strategies include inhibition of HSC proliferation or stimulation of HSC apoptosis, downregulation of collagen production or promotion of its degradation, administration of cytokines, and infusion of mesenchymal stem cells. In this review, we summarize the latest advances in our understanding of the mechanisms of HSC activation and possible antifibrotic therapeutic strategies.
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Affiliation(s)
- Jing-Ting Li
- Department of Pharmacology, Basic Medical School of Wuhan University, Luojia Hill, Wuhan 430071, China
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19
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Morsczeck C, Schmalz G, Reichert TE, Völlner F, Galler K, Driemel O. Somatic stem cells for regenerative dentistry. Clin Oral Investig 2008; 12:113-118. [PMID: 18172700 DOI: 10.1007/s00784-007-0170-8] [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] [Received: 07/10/2007] [Accepted: 11/27/2007] [Indexed: 02/07/2023]
Abstract
Complex human tissues harbour stem cells and/or precursor cells, which are responsible for tissue development or repair. Recently, dental tissues such as periodontal ligament (PDL), dental papilla or dental follicle have been identified as easily accessible sources of undifferentiated cells. The dental stem cell biology might provide meaningful insights into the development of dental tissues and cellular differentiation processes. Dental stem cells could also be feasible tools for dental tissue engineering. Constructing complex structures like a periodontium, which provides the functional connection between a tooth or an implant and the surrounding jaw, could effectively improve modern dentistry. Dental precursor cells are attractive for novel approaches to treat diseases like periodontitis, dental caries or to improve dental pulp healing and the regeneration of craniofacial bone and teeth. These cells are easily accessible and, in contrast to bone-marrow-derived mesenchymal stem cells, are more closely related to dental tissues. This review gives a short overview of stem cells of dental origin.
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20
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Sun T, Sun BC, Ni CS, Zhao XL, Wang XH, Qie S, Zhang DF, Gu Q, Qi H, Zhao N. Pilot study on the interaction between B16 melanoma cell-line and bone-marrow derived mesenchymal stem cells. Cancer Lett 2008; 263:35-43. [PMID: 18234417 DOI: 10.1016/j.canlet.2007.12.015] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2007] [Revised: 12/04/2007] [Accepted: 12/05/2007] [Indexed: 10/22/2022]
Abstract
Bone-marrow derived mesenchymal stem cells (BMSCs) have the potential to differentiate into osteocytes, chondrocytes, adipocytes and endothelial cells. The interaction between BMSCs and epithelial tumor cell was enhanced on proliferation. Our previous study had shown that BMSCs maybe participate in angiogenesis in melanoma in vivo. The aim of this study was to investigate the interaction between B16 melanoma cells and BMSCs in vitro, the mechanism of BMSCs participating in melanoma angiogenesis in vivo is unclear, so a co-culture system containing BMSCs and B16 melanoma cells, based on transwell indirect model, was established, and the interaction between BMSCs and B16 melanoma cells was studied in vitro. In our study, BMSCs were generated out of bone marrow from C57 mouse, isolated BMSCs were positive for the markers CD105, CD90, CD73, CD44 and CD166 and negative for endothelial markers, which acquired endothelial phenotype (including the expression of VEGFR-1, VEGFR-2, Factor VIII) after co-culture with B16 melanoma cells; at the same time, B16 melanoma cells also up-regulated the expression of VEGF-a, VEGFR-1, VEGFR-2 and Factor VIII. The proliferation rate of B16 melanoma cells and BMSCs were also found to be increased. We could show the differentiation of BMSCs into cells with phenotypic features of endothelial cells. BMSCs promoted proliferation of tumor cells and improved the microenvironment in tumor. Our study suggests that the BMSCs may play an important role in tumor angiogenesis.
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Affiliation(s)
- Tao Sun
- Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin 300060, China
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21
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Morsczeck C, Reichert TE, Völlner F, Gerlach T, Driemel O. [The state of the art in human dental stem cell research]. MUND-, KIEFER- UND GESICHTSCHIRURGIE : MKG 2007; 11:259-266. [PMID: 17846805 DOI: 10.1007/s10006-007-0071-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2007] [Accepted: 08/07/2007] [Indexed: 02/06/2023]
Abstract
This review article arranges the current results of stem cell biology for their use in dentistry. There are different types of stem cells, which are applicable for dental treatments. The use of embryonic stem cells, whose possibilities for breeding an artificial tooth were hardly evaluated, is however ethically precarious. On the other side the ethically harmless adult stem cells, which were isolated for example from bone marrow, were little examined for their capability of differentiation into dental tissues. Therefore their forthcoming use in dentistry is rather improbable. However, dental ectomesenchymal stem cells are more promising for dentistry in future. For example dental pulp stem cells (DPSCs) are capable to differentiate into dentin under in vitro conditions. Moreover it is possible to use periodontal ligament (PDL) stem cells and dental follicle precursors for periodontal tissue differentiations in vitro. Recently new populations of stem cells were isolated from the dental pulp and the PDL. These cells distinguish from the initially isolated DPSCs and PDL stem cells in growth and cell differentiation. Therefore stem cell markers are very important for the characterization of dental stem cells. A significant marker for dental stem cells is STRO-1, which is also a marker for bone marrow derived mesenchymal stem cells. Nonetheless dental stem cells are CD45 negative and they express rarely hematopoietic stem cell markers. These research results plead for the participation of dental stem cells in dental practice in future.
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Affiliation(s)
- Christian Morsczeck
- Institut für Humangenetik, Universität Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.
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22
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Snykers S, Vanhaecke T, De Becker A, Papeleu P, Vinken M, Van Riet I, Rogiers V. Chromatin remodeling agent trichostatin A: a key-factor in the hepatic differentiation of human mesenchymal stem cells derived of adult bone marrow. BMC DEVELOPMENTAL BIOLOGY 2007; 7:24. [PMID: 17407549 PMCID: PMC1852547 DOI: 10.1186/1471-213x-7-24] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2006] [Accepted: 04/02/2007] [Indexed: 02/05/2023]
Abstract
Background The capability of human mesenchymal stem cells (hMSC) derived of adult bone marrow to undergo in vitro hepatic differentiation was investigated. Results Exposure of hMSC to a cocktail of hepatogenic factors [(fibroblast growth factor-4 (FGF-4), hepatocyte growth factor (HGF), insulin-transferrin-sodium-selenite (ITS) and dexamethasone)] failed to induce hepatic differentiation. Sequential exposure to these factors (FGF-4, followed by HGF, followed by HGF+ITS+dexamethasone), however, resembling the order of secretion during liver embryogenesis, induced both glycogen-storage and cytokeratin (CK)18 expression. Additional exposure of the cells to trichostatin A (TSA) considerably improved endodermal differentiation, as evidenced by acquisition of an epithelial morphology, chronological expression of hepatic proteins, including hepatocyte-nuclear factor (HNF)-3β, alpha-fetoprotein (AFP), CK18, albumin (ALB), HNF1α, multidrug resistance-associated protein (MRP)2 and CCAAT-enhancer binding protein (C/EBP)α, and functional maturation, i.e. upregulated ALB secretion, urea production and inducible cytochrome P450 (CYP)-dependent activity. Conclusion hMSC are able to undergo mesenchymal-to-epithelial transition. TSA is hereby essential to promote differentiation of hMSC towards functional hepatocyte-like cells.
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Affiliation(s)
- Sarah Snykers
- Dept. Toxicology., Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090, Brussels, Belgium
| | - Tamara Vanhaecke
- Dept. Toxicology., Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090, Brussels, Belgium
| | - Ann De Becker
- Dept. Medical Oncology and Hematology, Stem Cell Laboratory, Academic. Hospital, Vrije Universiteit Brussel, Laarbeeklaan 101, B-1090, Brussels, Belgium
| | - Peggy Papeleu
- Dept. Toxicology., Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090, Brussels, Belgium
| | - Mathieu Vinken
- Dept. Toxicology., Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090, Brussels, Belgium
| | - Ivan Van Riet
- Dept. Medical Oncology and Hematology, Stem Cell Laboratory, Academic. Hospital, Vrije Universiteit Brussel, Laarbeeklaan 101, B-1090, Brussels, Belgium
| | - Vera Rogiers
- Dept. Toxicology., Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090, Brussels, Belgium
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Cao BQ, Lin JZ, Zhong YS, Huang SB, Lin N, Tang ZF, Chen R, Xiang P, Xu RY. Contribution of mononuclear bone marrow cells to carbon tetrachloride-induced liver fibrosis in rats. World J Gastroenterol 2007; 13:1851-4; discussion 1854-6. [PMID: 17465480 PMCID: PMC4149966 DOI: 10.3748/wjg.v13.i12.1851] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [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 study the inhibitory effect of mononuclear bone marrow cell (BMC) transplantation on carbon tetrachloride (CCl4) -induced liver fibrosis in rats.
METHODS: Rat liver fibrosis models were induced by CCl4 and alcohol administration. After 8 wk, twenty rats were randomly allocated into treatment group (n = 10) and control group (n = 10). BMC were infused into the rats in treatment group via the portal vein, while heparinized saline was infused in control group. CCl4 was hypodermically injected into the rats twice a week for 4 wk. At the end of wk 12, all rats were humanely sacrificed. Liver samples were taken and stained with HE or Masson trichrome. The general conditions, liver fibrosis (hydroxyproline and collagen fibre) and liver pathological grades in rats were evaluated.
RESULTS: The general conditions of the rats in treatment group improved markedly, but not in control group. Hydroxyproline was 504.6 ± 128.8 μg/g in treatment group, and 596.0 ± 341.8 μg/g in control group. The percentage of collagen fibre was 3.75% ± 0.98% in treatment group and 5.02% ± 0.44% in control group. There was a significant difference between the two groups (P < 0.05). Liver pathological grade decreased from grade IV to grade III partially in treatment group (P < 0.05) with no obvious improvement in control group (P > 0.05). There was a significant difference between treatment group and control group (P < 0.05).
CONCLUSION: Transplantation of BMC can improve liver fibrosis due to chronic liver injury in rats.
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Affiliation(s)
- Bao-Qiang Cao
- Department of Hepatobility Surgery, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
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Hüttmann A, Gutersohn A, Noppeney R, Neumann T, Erbel R, Dührsen U. Rapid succession of peripheral blood progenitor cell mobilization cycles in patients with chronic heart failure: effects on the hematopoietic system. Transfusion 2006; 46:1424-31. [PMID: 16934081 DOI: 10.1111/j.1537-2995.2006.00912.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
BACKGROUND Circulating hematopoietic peripheral blood progenitor cells (PBPCs) may contribute to the regeneration of nonhematopoietic organs. An increase in circulating PBPC numbers may enhance this process. Therefore, an exploratory trial of repeated PBPC mobilization in patients with chronic heart failure was conducted. The safety and cardiovascular efficacy data have been described elsewhere. In the hematopoietic system, the trial offered an opportunity to study several new aspects of granulocyte-colony-stimulating factor (G-CSF) action. STUDY DESIGN AND METHODS Fourteen male patients with chronic heart failure were treated successively with G-CSF (four 10-day treatment periods interrupted by treatment-free intervals of equal length; daily dose adjustment to maintain a white blood cell [WBC] count of 45 x 10(9)-50 x 10(9)/L). RESULTS G-CSF induced a rapid increase in cells of all WBC lineages with return to levels equal to (neutrophilic, eosinophilic, and basophilic granulocytes) or lower than those before treatment (monocytes, lymphocytes) during the treatment-free intervals. Red cell counts remained unchanged, but platelet counts decreased followed by rebound thrombocytosis. The extent of CD34+ cell mobilization was highly variable. For each patient, the changes induced were identical through all cycles, but the G-CSF dose required in the first cycle was significantly higher than in subsequent cycles. In the cohort of patients, an inverse correlation was observed between the WBC level reached and the dose of G-CSF administered. CONCLUSIONS Rapid alternation between PBPC mobilization and recovery periods is feasible, with identical alterations in all treatment cycles. G-CSF responsiveness varies among patients and is increased by pretreatment with G-CSF.
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Affiliation(s)
- Andreas Hüttmann
- Hematology Clinic and the Cardiology Clinic, Center for Internal Medicine, University Hospital, Essen, Germany.
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Snykers S, Vanhaecke T, Papeleu P, Luttun A, Jiang Y, Vander Heyden Y, Verfaillie C, Rogiers V. Sequential exposure to cytokines reflecting embryogenesis: the key for in vitro differentiation of adult bone marrow stem cells into functional hepatocyte-like cells. Toxicol Sci 2006; 94:330-41; discussion 235-9. [PMID: 16840566 DOI: 10.1093/toxsci/kfl058] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Differentiation of adult bone marrow stem cells (BMSC) into hepatocyte-like cells is commonly performed by continuous exposure to a cytokines-cocktail. Here, it is shown that the differentiation efficacy in vitro can be considerably enhanced by sequential addition of liver-specific factors (fibroblast growth factor-4, hepatocyte growth factor, insulin-transferrin-sodium selenite, and dexamethasone) in a time-dependent order that closely resembles the secretion pattern during in vivo liver embryogenesis. Quantitative RT-PCR analysis and immunocytochemistry showed that, upon sequential exposure to liver-specific factors, different stages of hepatocyte differentiation, as seen during liver embryogenesis, can be mimicked. Indeed, expression of the early hepatocyte markers alpha-fetoprotein and hepatocyte nuclear factor (HNF)3beta decreased as differentiation progressed, whereas levels of the late liver-specific markers albumin (ALB), cytokeratin (CK)18, and HNF1alpha were gradually upregulated. In contrast, cocktail treatment did not significantly alter the expression pattern of the hepatic markers. Moreover, sequentially exposed cells featured highly differentiated hepatic functions, including ALB secretion, glycogen storage, urea production, and inducible cytochrome P450-dependent activity, far more efficiently compared to the cocktail condition. In conclusion, sequential induction of the differentiation process, analogous to in vivo liver development, is crucial for in vitro differentiation of adult rat BMSC into functional hepatocyte-like cells. This model may not only be applicable for in vitro studies of endoderm differentiation but it also provides a "virtually unlimited" source of functional hepatocytes, suitable for preclinical pharmacological research and testing, and cell and organ development.
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Affiliation(s)
- Sarah Snykers
- Department of Toxicology, Vrije Universiteit Brussel, B-1090 Brussels, Belgium.
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Ueno T, Nakamura T, Torimura T, Sata M. Angiogenic cell therapy for hepatic fibrosis. Med Mol Morphol 2006; 39:16-21. [PMID: 16575510 DOI: 10.1007/s00795-006-0311-1] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2006] [Accepted: 01/19/2006] [Indexed: 01/01/2023]
Abstract
Progression of liver fibrosis has been linked with injuries associated with hypoxia and neovascularization. Neovascularization consists of angiogenesis and vasculogenesis, representing formation of blood vessels by differentiation of endothelial progenitor cells (EPCs). We investigated antifibrogenic and regenerative effects of EPC transplantation in chronic liver injury. Rat EPCs were isolated from bone marrow cells and examined in vitro for lineage markers. Recipient rats were injected intraperitoneally with dimethylnitrosamine (DMN) three times weekly for 4 weeks, plus EPC transplantation once weekly for 4 weeks. Transplanted rats showed suppression of liver fibrogenesis. Expression of growth factors promoting liver regeneration such as hepatocyte growth factor (HGF), transforming growth factor (TGF)-alpha, epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) was increased in transplanted rats, together with hepatocyte proliferation. Normal liver function parameters such as transaminase, total bilirubin, total protein, and albumin were maintained in transplanted rats. EPC transplantation is effective not only for preventing liver fibrosis but also for promoting regeneration in chronically damaged livers. Also, recently it has been reported that green fluorescent protein-positive bone marrow cells contribute to the liver tissue repair of fibrosis model rats. EPC transplantation might become an alternative if further preclinical investigation finds it to be effective in severely cirrhotic livers.
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Affiliation(s)
- Takato Ueno
- Research Center for Innovative Cancer Therapy and Center of the 21st Century COE Program for Medical Science, Kurume University School of Medicine, Japan.
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Sun TT. Altered phenotype of cultured urothelial and other stratified epithelial cells: implications for wound healing. Am J Physiol Renal Physiol 2006; 291:F9-21. [PMID: 16609152 DOI: 10.1152/ajprenal.00035.2006] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
The differentiation of cultured stratified epithelial cells can deviate significantly from that of normal epithelium, leading to suggestions that cultured cells undergo abnormal differentiation, or a truncated differentiation. Thus cultured epidermal and corneal epithelial cells stop synthesizing their tissue-specific keratin pair K1/K10 and K3/K12, respectively. The replacement of these keratins in the suprabasal compartment by K6/K16 keratins that are made by all stratified squamous epithelia during hyperplasia rules out a truncated differentiation. Importantly, the keratin pattern of in vivo corneal epithelium undergoing wound repair mimics that of cultured rabbit corneal epithelial cells. Although cultured urothelial cells continue to synthesize uroplakins, which normally form two-dimensional crystalline urothelial plaques covering almost the entire apical urothelial surface, these proteins do not assemble into crystals in cultured cells. Cultured epithelial cells can, however, rapidly regain normal differentiation on the removal of mitogenic stimuli, the use of a suitable extracellular matrix, or the transplantation of the cells to an in vivo, nonmitogenic environment. These data suggest that cultured epithelial cells adopt altered differentiation patterns mimicking in vivo regenerating or hyperplastic epithelia. Blocking the synthesis of tissue-specific differentiation products, such as the K1 and K10 keratins designed to form extensive disulfide cross-links in cornified cells, or the assembly of uroplakin plaques allows epithelial cells to better migrate and proliferate, activities that are of overriding importance during wound repair. Cultured urothelial and other stratified epithelial cells provide excellent models for studying the regulation of the synthesis and assembly of differentiation products, a key cellular process during epithelial wound repair.
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Affiliation(s)
- Tung-Tien Sun
- Epithelial Biology Unit, Department of Dermatology, New York University Cancer Institute, Medical School, 550 First Ave., New York, NY 10016, USA.
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Abstract
Stem cells are quickly coming into focus of much biomedical research eventually aiming at the therapeutic applications for various disorders and trauma. It is important, however, to keep in mind the difference between the embryonic stem cells, somatic stem cells and somatic precursor cells when considering potential clinical applications. Here we provide the review of the current status of stem cell field and discuss the potential of therapeutic applications for blood and Immune system disorders, multiple sclerosis, hypoxic-ischemic brain injury and brain tumors. For the complimentary information about various stem cells and their properties we recommend consulting the National Institutes of Health stem cell resources (http://stemcells.nih.gov/info/basics).
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Hüttmann A, Dührsen U, Heydarian K, Klein-Hitpass L, Boes T, Boyd AW, Li CL. Gene expression profiles in murine hematopoietic stem cells revisited: analysis of cDNA libraries reveals high levels of translational and metabolic activities. Stem Cells 2006; 24:1719-27. [PMID: 16574753 DOI: 10.1634/stemcells.2005-0486] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Gene expression studies from hematopoietic stem cell (HSC) populations purified to variable degrees have defined a set of stemness genes. Unexpectedly, results also hinted toward a HSC chromatin poised in a wide-open state. With the aim of providing a robust tool for further studies into the molecular biology of HSCs, the studies herein describe the construction and comparative molecular analysis of lambda-phage cDNA libraries from highly purified HSCs that retained their long-term repopulating activities (long-term HSCs [LT-HSCs]) and from short-term repopulating HSCs that were largely depleted of these activities. Microarray analysis of the libraries confirmed the previous results but also revealed an unforeseen preferential expression of translation- and metabolism-associated genes in the LT-HSCs. Therefore, these data indicate that HSCs are quiescent only in regard of proliferative activities but are in a state of readiness to provide the metabolic and translational activities required after induction of proliferation and exit from the HSC pool.
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Hüttmann A, Dührsen U, Stypmann J, Noppeney R, Nückel H, Neumann T, Gutersohn A, Nikol S, Erbel R. Granulocyte colony-stimulating factor-induced blood stem cell mobilisation in patients with chronic heart failure--Feasibility, safety and effects on exercise tolerance and cardiac function. Basic Res Cardiol 2005; 101:78-86. [PMID: 16237506 DOI: 10.1007/s00395-005-0556-1] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2005] [Revised: 08/29/2005] [Accepted: 09/23/2005] [Indexed: 11/25/2022]
Abstract
Bone marrow-derived stem cells may contribute to the regeneration of non-haematopoietic organs. In order to test whether an increase in circulating stem cell numbers improves impaired myocardial function we treated 16 male patients with chronic heart failure due to dilated (DCM; n = 7) or ischaemic cardiomyopathy (ICM; n = 9) with the stem cell mobilising cytokine granulocyte colony-stimulating factor (G-CSF; four 10-day treatment periods interrupted by treatment-free intervals of equal length). Safety and efficacy analyses were performed at regular intervals. Peak CD34+ cell counts remained constant from cycle to cycle. Cardiac side effects in ICM patients included occasional episodes of dyspnea or angina and one episode of fatal ventricular fibrillation. Nine (4 DCM, 5 ICM) of 12 patients receiving four full G-CSF cycles experienced an improvement by one New York Heart Association (NYHA) class and a statistically significant increase in six-minute walking distance. By contrast, none of 8 ICM historical controls had a change in NYHA class during a similar time period. Statistically significant changes in echocardiographic parameters were not recorded. Sequential administration of G-CSF is feasible and possibly effective in improving physical performance in patients with chronic heart failure. Patients with ICM may be at risk of increased angina and arrhythmias.
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Affiliation(s)
- Andreas Hüttmann
- Klinik für Hämatologie, Universitätsklinikum Essen, Hufelandstrasse 55, 45122 Essen, Germany
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Bossolasco P, Cova L, Calzarossa C, Rimoldi SG, Borsotti C, Deliliers GL, Silani V, Soligo D, Polli E. Neuro-glial differentiation of human bone marrow stem cells in vitro. Exp Neurol 2005; 193:312-25. [PMID: 15869934 DOI: 10.1016/j.expneurol.2004.12.013] [Citation(s) in RCA: 147] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2004] [Revised: 07/09/2004] [Accepted: 12/01/2004] [Indexed: 01/09/2023]
Abstract
Bone marrow (BM) is a rich source of stem cells and may represent a valid alternative to neural or embryonic cells in replacing autologous damaged tissues for neurodegenerative diseases. The purpose of the present study is to identify human adult BM progenitor cells capable of neuro-glial differentiation and to develop effective protocols of trans-differentiation to surmount the hematopoietic commitment in vitro. Heterogeneous cell populations such as whole BM, low-density mononuclear and mesenchymal stem (MSCs), and several immunomagnetically separated cell populations were investigated. Among them, MSCs and CD90+ cells were demonstrated to express neuro-glial transcripts before any treatment. Several culture conditions with the addition of stem cell or astroblast conditioned media, different concentrations of serum, growth factors, and supplements, used alone or in combinations, were demonstrated to alter the cellular morphology in some cell subpopulations. In particular, MSCs and CD90+ cells acquired astrocytic and neuron-like morphologies in specific culture conditions. They expressed several neuro-glial specific markers by RT-PCR and glial fibrillary acid protein by immunocytochemistry after co-culture with astroblasts, both in the absence or presence of cell contact. In addition, floating neurosphere-like clones have been observed when CD90+ cells were grown in neural specific media. In conclusion, among the large variety of human adult BM cell populations analyzed, we demonstrated the in vitro neuro-glial potential of both the MSC and CD90+ subset of cells. Moreover, unidentified soluble factors provided by the conditioned media and cellular contacts in co-culture systems were effective in inducing the neuro-glial phenotype, further supporting the adult BM neural differentiative capability.
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Abstract
Cardiomyocytes respond to physiological or pathological stress only by hypertrophy and not by an increase in the number of functioning cardiomyocytes. However, recent evidence suggests that adult cardiomyocytes have the ability, albeit limited, to divide to compensate for the cardiomyocyte loss in the event of myocardial injury. Similarly, the presence of stem cells in the myocardium is a good omen. Their activation to participate in the repair process is, however, hindered by some as-yet-undetermined biological impediments. The rationale behind the use of adult stem cell transplantation is to supplement the inadequacies of the intrinsic repair mechanism of the heart and compensate for the cardiomyocyte loss in the event of injury. Various cell types including embryonic, fetal, and adult cardiomyocytes, smooth muscle cells, and stable cell lines have been used to augment the declining cardiomyocyte number and cardiac function. More recently, the focus has been shifted to the use of autologous skeletal myoblasts and bone marrow-derived stem cells. This review is a synopsis of some interesting aspects of the fast-emerging field of bone marrow-derived stem cell therapy for cardiac repair.
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Affiliation(s)
- Husnain Kh Haider
- Dept. of Pathology and Laboratory of Medicine, 231-Albert Sabinway, Univ. of Cincinnati, Cinncinati, OH 45267-0529, USA.
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Sun B, Zhang S, Ni C, Zhang D, Liu Y, Zhang W, Zhao X, Zhao C, Shi M. Correlation Between Melanoma Angiogenesis and the Mesenchymal Stem Cells and Endothelial Progenitor Cells Derived from Bone Marrow. Stem Cells Dev 2005; 14:292-8. [PMID: 15969624 DOI: 10.1089/scd.2005.14.292] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Endothelial progenitor cells (EPC) reportedly differentiate into endothelial cells and participate in angiogenesis, including neovascularization at sites of neoplastic development. Recently, we reported that Flk+/CD31-/CD34- mesenchymal stem cells (MSC) possess the potential of differentiating into both endothelial and hematopoietic cells. We hypothesized that these MSC contribute to tumor angiogenesis. This concept is controversial and this study was undertaken to address this controversy. We show that progeny of human MSC as well as differentiated endothelial cells possess the ability to participate in tumor angiogenesis. When human marrow-derived MSC were injected into tail veins of severe combined immunodeficient (SCID) mice engrafted with human malignant melanoma, human cells incorporated into tumor vessels. Moreover, human-derived endothelial cells were identified in the walls of mouse tumor vessels by immunohistology. We report for the first time that similar results are obtained when mice carrying malignant melanoma are injected with differentiated human endothelial cells. Thus, we demonstrate that both differentiated endothelial cells from tissue peripheral to that of a tumor as well as progeny of human MSC have similar capacities to participate in angiogenesis.
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Affiliation(s)
- Baocun Sun
- Department of Pathology, TianJin Cancer Hospital, TianJin Medical University, TianJin 300060, China
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Lakshmipathy U, Pelacho B, Sudo K, Linehan JL, Coucouvanis E, Kaufman DS, Verfaillie CM. Efficient transfection of embryonic and adult stem cells. ACTA ACUST UNITED AC 2005; 22:531-43. [PMID: 15277699 DOI: 10.1634/stemcells.22-4-531] [Citation(s) in RCA: 148] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The ability of embryonic stem cells and adult stem cells to differentiate into specific cell types holds immense potential for therapeutic use in cell and gene therapy. Realization of this potential depends on efficient and optimized protocols for genetic manipulation of stem cells. In the study reported here, we demonstrate the use of nucleofection as a method to introduce plasmid DNA into embryonic and adult stem cells with significantly greater efficiency than electroporation or lipid-based transfection methods have. Using enhanced green fluorescent protein (eGFP) as a reporter gene, mouse embryonic stem cells were transfected both transiently and stably at a rate nearly 10-fold higher than conventional methods. The transfected cells retained their stem cell properties, including continued expression of the stem cell markers SSEA1, Oct4, and Rex1; formation of embryoid bodies; differentiation into cardiomyocytes in the presence of appropriate inducers; and, when injected into developing blastocysts, contribution to chimeras. Higher levels of transfection were also obtained with human embryonic carcinoma and human embryonic stem cells. Particularly hard-to-transfect adult stem cells, including bone marrow and multipotent adult progenitor cells, were also transfected efficiently by the method of nucleofection. Based on our results, we conclude that nucleofection is superior to currently available methods for introducing plasmid DNA into a variety of embryonic and adult stem cells. The high levels of transfection achieved by nucleofection will enable its use as a rapid screening tool to evaluate the effect of ectopically expressed transcription factors on tissue-specific differentiation of stem cells.
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Affiliation(s)
- Uma Lakshmipathy
- Stem Cell Institute, Hematology, Oncology and Transplantation Division, University of Minnesota, Minneapolis 55455, USA
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Abstract
Experimental biology and medicine work with stem cells more than twenty years. The method discovered for in vitro culture of human embryonal stem cells acquired at abortions or from "surplus" embryos left from in vitro fertilization, evoked immediately ideas on the possibility to aim development and differentiation of these cells at regeneration of damaged tissues. Recently, several surprising observations proved that even tissue-specific (multipotent) stem cells are capable, under suitable conditions, of producing a whole spectrum of cell types, regardless, whether these tissues are derived from the same germ layer or not. This ability is frequently called stem cell plasticity but other authors also use different names - "non-orthodox differentiation" or "transdifferentiation". In this paper we wish to raise several important questions and problems related to this theme. Let us remind some of them: Is it possible to force cells of one-type tissue to look and act as cells of another tissue? Are these changes natural? Could these transformations be used to treat diseases? What about the bioethic issue? However, the most serious task "still remains to be solved - how to detect, harvest and culture stem cells for therapy of certain diseases".
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Affiliation(s)
- S Filip
- Department of Oncology and Radiotherapy, Charles University Hospital, Sokolska Street 480, 500 05 Hradec Králové, Czech Republic.
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Shackel N, Rockey D. In pursuit of the "Holy Grail"--stem cells, hepatic injury, fibrogenesis and repair. Hepatology 2005; 41:16-8. [PMID: 15690475 DOI: 10.1002/hep.20551] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Abstract
Deer antlers are cranial appendages that develop after birth as extensions of a permanent protuberance (pedicle) on the frontal bone. Pedicles and antlers originate from a specialized region of the frontal bone; the 'antlerogeneic periosteum' and the systemic cue which triggers their development in the fawn is an increase in circulating androgen. These primary antlers are then shed and regenerated the following year in a larger, more complex form. Antler growth is extremely rapid-an adult red deer can produce a pair of antlers weighing approximately 30kg in three months, and involves both endochondral and intramembranous ossification. Since antlers are sexual secondary characteristics, their annual cycles of growth have evolved to be closely coordinated to the reproductive cycle which, in temperate species, is linked to the photoperiod. Cessation of antler growth and death of the overlying skin (velvet) coincides with a rise in circulating testosterone as the autumn breeding season approaches. The 'dead' antlers remain attached to the pedicle until they are shed (cast) the following spring when circulating testosterone levels fall. In red deer, the species that we study, casting of the old set of antlers is followed immediately by growth of the new set. Although the anatomy of antler growth and the endocrine changes associated with it have been well documented, the molecular mechanisms involved remain poorly understood. The case for continuing to decipher them remains compelling, despite the obvious limitations of using deer as an experimental model, because this research will help provide insight into why humans and other mammals have lost the ability to regenerate organs. From the information so far available, it would appear that the signaling pathways that control the development of skeletal elements are recapitulated in regenerating antlers. This apparent lack of any specific 'antlerogenic molecular machinery' suggests that the secret of deers' ability to regenerate antlers lies in the particular cues to which multipotential progenitor/stem cells in an antler's 'regeneration territory' are exposed. This in turn suggests that with appropriate manipulation of the environment, pluripotential cells in other adult mammalian tissues could be stimulated to increase the healing capacity of organs, even if not to regenerate them completely. The need for replacement organs in humans is substantial. The benefits of increasing individuals' own capacity for regeneration and repair are self evident.
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Affiliation(s)
- Joanna Price
- Department of Veterinary Basic Sciences, The Royal Veterinary College, London NW1 OTU, United Kingdom
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Affiliation(s)
- Timothy S Sadiq
- Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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A microenvironment, rather than chemical, initiates the cardiomyogenic differentiation of marrow stromal cells. ACTA ACUST UNITED AC 2004. [DOI: 10.1007/bf02830454] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Affiliation(s)
- Nelson Fausto
- Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.
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Abstract
Bone marrow (BM) contains hematopoietic stem cells, which differentiate into all mature blood cells, and marrow stromal cells that provide the microenvironment for hematopoietic stem/progenitor cells along with the capability to differentiate into mature cells of multiple mesenchymal tissues including fat, bone, and cartilage. Recent studies indicate that adult BM also contains cells that can differentiate into nonhematopoietic cells of ectodermal, mesodermal, and endodermal tissues other than hematopoietic tissues, including liver, pancreas, kidney, lung, skin, gastrointestinal tract, heart, skeletal muscles, and neural tissues. Studies reporting the multipotentiality of BM cells have become a focus of interest because they suggest that clinical applications could be at hand using easily obtainable cells in the treatment of tissue damage or degenerative diseases. Presently, however, definitive evidence explaining the mechanism of this multipotentiality of BM stem cells is lacking. In this review, we summarize recent progress and controversies in investigation of the multipotentiality of adult BM-derived stem cells to differentiate into nonhematopoietic tissues.
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Affiliation(s)
- Toshio Heike
- Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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