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Gulubova M, Tolekova A, Berbatov D, Aydogdu N. Development of pancreatic islet cells in the extrahepatic bile ducts of rats with experimentally-induced metabolic syndrome. Arch Physiol Biochem 2024; 130:669-677. [PMID: 37651586 DOI: 10.1080/13813455.2023.2252205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 07/27/2023] [Accepted: 08/21/2023] [Indexed: 09/02/2023]
Abstract
CONTEXT There is data about the existence of some endocrine cells in the epithelial layer of the bile duct in humans and rats. OBJECTIVE We evaluated Ghrelin-, Insulin-, Glucagon- and Somatostatin-positive cells in peribiliary glands, mast cells, and nerve fibres. MATERIALS AND METHODS Wistar rats were used for dietary manipulation with a 15% fructose solution for 12 weeks. Tissue samples were elaborated with immunohistochemistry for Insulin, Glucagon, Ghrelin, and Somatostatin. Glucose and lipid parameters were studied. RESULTS In treated animals, Ghrelin+ and Insulin+ cells in perybiliary glands (PBGs) were significantly increased. In the male fructose group there was a significant increase of the homeostasis model assessment insulin resistance (HOMA-IR). CONCLUSIONS Stem/progenitor cells in extrahepatic bile tree (EHBT) could be a source of Insulin-producing cells in metabolic syndrome. Fructose treatment induces the increase of Ghrelin+ and Insulin+ cells in PBGs and the elevation of Insulin and Ghrelin plasma concentration.
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Affiliation(s)
- Maya Gulubova
- Department of pathology, Trakia University, Stara Zagora, Bulgaria
| | - Anna Tolekova
- Medical College, Trakia University, Stara Zagora, Bulgaria
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Toba H, Takai S. Exploring the roles of SPARC as a proinflammatory factor and its potential as a novel therapeutic target against cardiovascular disease. Am J Physiol Heart Circ Physiol 2024; 327:H1174-H1186. [PMID: 39269452 DOI: 10.1152/ajpheart.00565.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 09/09/2024] [Accepted: 09/09/2024] [Indexed: 09/15/2024]
Abstract
Cardiovascular disease (CVD) is a leading cause of death worldwide, and the number of patients with CVD continues to increase despite extensive research and developments in this field. Chronic inflammation is a pivotal pathological component of CVD, and unveiling new proinflammatory factors will help devise novel preventive and therapeutic strategies. The extracellular matrix (ECM) not only provides structural support between cells but also contributes to cellular functions. Secreted protein acidic and rich in cysteine (SPARC) is a collagen-binding matricellular protein that is particularly induced during development and tissue remodeling. A proinflammatory role for SPARC has been demonstrated in various animal models, such as in the lipopolysaccharide-induced footpad model and dextran sodium sulfate-induced colitis model. Recent clinical studies reported a positive correlation between elevated plasma SPARC levels and hypertension, obesity, and the inflammatory marker high-sensitive C-reactive protein. In addition, SPARC gene deletion attenuates the cardiac injury induced by aging, myocardial infarction, and pressure load, suggesting that SPARC has deleterious effects on CVD. This review summarizes the regulatory and proinflammatory mechanisms of SPARC on CVD, chronic kidney disease (CKD), and cerebrovascular disease and discusses the rationale behind measuring SPARC as a biomarker of CVD and the effects of inhibition of SPARC in the prevention and treatment of CVD.
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Affiliation(s)
- Hiroe Toba
- Division of Pathological Sciences, Department of Clinical Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan
- Department of Pharmacology, Educational Foundation of Osaka Medical and Pharmacological University, Takatsuki, Japan
| | - Shinji Takai
- Department of Pharmacology, Educational Foundation of Osaka Medical and Pharmacological University, Takatsuki, Japan
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3
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Okano J, Nakagawa T, Kojima H. Plasticity of bone marrow-derived cell differentiation depending on microenvironments in the skin. Front Physiol 2024; 15:1391640. [PMID: 38699142 PMCID: PMC11063383 DOI: 10.3389/fphys.2024.1391640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 04/04/2024] [Indexed: 05/05/2024] Open
Abstract
Bone marrow-derived cells (BMDCs) are heterogeneous populations in which not only pluripotent stem cells, namely, hematopoietic stem cells (HSCs), mesenchymal stem cells (MSC) but also endothelial progenitor cells (EPC) are involved. BMDCs contribute to the maintenance of homeostasis and recovery from disrupted homeostasis as the immune, endocrine, and nervous systems. The skin is the largest organ in which various tissues, such as the epidermis, dermis, skin appendages (i.e., hair follicles), fats, muscles, and vessels, are tightly and systematically packed. It functions as a physical barrier to block the invasion of harmful substances and pathogenic microorganisms and properly regulate water evaporation. The skin is exposed to injuries from external stimuli because it is the outermost layer and owing to its specificity. Recovery from physical injuries and DNA mutations occurs constantly in the skin, but medical treatments are required for impaired wound healing. Recently, conservative treatments utilizing scaffolds have attracted attention as alternatives to surgical therapy, which is highly invasive. Against this background, numerous scaffolds are available in a clinical setting, although they have not surpassed surgery because of their distinct disadvantages. Here, we discuss the plasticity of BMDCs in the skin to maintain homeostasis, in addition to their critical roles on recovery from disrupted homeostasis. We also share our perspective on how scaffolds can be developed to establish scaffolds beyond surgery to regenerate skin structure during wound healing by maximally utilizing the plasticity of BMDCs.
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Affiliation(s)
- Junko Okano
- Department of Plastic and Reconstructive Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Takahiko Nakagawa
- Department of Regenerative Medicine Development, Shiga University of Medical Science, Otsu, Japan
| | - Hideto Kojima
- Department of Regenerative Medicine Development, Shiga University of Medical Science, Otsu, Japan
- Department of Biocommunication Development, Shiga University of Medical Science, Otsu, Japan
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Abidov M, Sokolova K, Danilova I, Baykenova M, Gette I, Mychlynina E, Aydin Ozgur B, Gurol AO, Yilmaz MT. Hepatic insulin synthesis increases in rat models of diabetes mellitus type 1 and 2 differently. PLoS One 2023; 18:e0294432. [PMID: 38019818 PMCID: PMC10686419 DOI: 10.1371/journal.pone.0294432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 11/01/2023] [Indexed: 12/01/2023] Open
Abstract
Insulin-positive (+) cells (IPCs), detected in multiple organs, are of great interest as a probable alternative to ameliorate pancreatic beta-cells dysfunction and insulin deficiency in diabetes. Liver is a potential source of IPCs due to it common embryological origin with pancreas. We previously demonstrated the presence of IPCs in the liver of healthy and diabetic rats, but detailed description and analysis of the factors, which potentially can induced ectopic hepatic expression of insulin in type 1 (T1D) and type 2 diabetes (T2D), were not performed. In present study we evaluate mass of hepatic IPCs in the rat models of T1D and T2D and discuss factors, which may stimulate it generation: glycaemia, organ injury, involving of hepatic stem/progenitor cell compartment, expression of transcription factors and inflammation. Quantity of IPCs in the liver was up by 1.7-fold in rats with T1D and 10-fold in T2D compared to non-diabetic (ND) rats. We concluded that ectopic hepatic expression of insulin gene is activated by combined action of a number of factors, with inflammation playing a decision role.
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Affiliation(s)
- Musa Abidov
- Institute of Immunopathology and Preventive Medicine, Ljubljana, Slovenia
| | - Ksenia Sokolova
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Yekaterinburg, Russian Federation
| | - Irina Danilova
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Yekaterinburg, Russian Federation
| | - Madina Baykenova
- Kostanay Oblast Tuberculosis Dispensary, Kostanay, Republic of Kazakhstan
| | - Irina Gette
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Yekaterinburg, Russian Federation
| | - Elena Mychlynina
- Institute of Immunology and Physiology, Ural Branch of the Russian Academy of Sciences, Yekaterinburg, Russian Federation
| | - Burcin Aydin Ozgur
- Department of Medical Biology and Genetics, Faculty of Medicine, Demiroglu Bilim University, Istanbul, Turkey
- Diabetes Application and Research Center, Demiroglu Bilim University, Istanbul, Turkey
| | - Ali Osman Gurol
- Department of Immunology, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
- Diabetes Application and Research Center, Istanbul University, Istanbul, Turkey
| | - M. Temel Yilmaz
- International Diabetes Center, Acibadem University, Istanbul, Turkey
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5
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Fujikawa H, Kojima H, Terashima T, Katagi M, Yayama T, Kumagai K, Mori K, Saito H, Imai S. Expression of proinflammatory cytokines and proinsulin by bone marrow-derived cells for fracture healing in long-term diabetic mice. BMC Musculoskelet Disord 2023; 24:585. [PMID: 37464323 DOI: 10.1186/s12891-023-06710-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 07/09/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND Diabetes mellitus (DM) causes bone dysfunction due to poor bone quality, leading to severe deterioration in patient of quality of life. The mechanisms of bone metabolism in DM remain unclear, although chemical and/or mechanical factors are known to disrupt the homeostasis of osteoblasts and osteoclasts. The purpose of this study was to identify the changes of osteoblasts and osteoclasts under long-term hyperglycaemic conditions, using a mouse fracture model of long-term hyperglycemia (LT-HG). METHODS C57BL/6J mice and green fluorescent protein (GFP) -positive bone marrow transplanted C57BL/6J mice with LT-HG, maintained under a state of hyperglycaemia for 2 months, were used in this study. After the experimental fracture, we examined the immunohistochemical expression of proinsulin and tumor necrosis factor (TNF) -α at the fracture site. C57BL/6J fracture model mice without hyperglycaemia were used as controls. RESULTS In the LT-HG mice, chondrocyte resorption was delayed, and osteoblasts showed an irregular arrangement at the callus site. The osteoclasts were scattered with a decrement in the number of nuclei. The expression of proinsulin was confirmed in bone marrow derived cells (BMDCs) with neovascularization 2 and 3 weeks after fracture. Immunopositivity for TNF-α was also confirmed in immature chondrocytes and BMDCs with neovascularization at 2 weeks, and the number of positive cells was not decreased at 3 weeks. Examination of GFP-grafted hyperglycaemic mice showed that the majority of cells at the fracture site were GFP-positive. Immunohistochemistry showed that the rate of double positives was 15% for GFP and proinsulin and 47% for GFP and TNF-α. CONCLUSION LT-HG induces an increase in the number of proinsulin and TNF-α positive cells derived from BMDCs. We suggest that proinsulin and TNF-α positive cells are involved in both bone formation and bone resorption after fracture under hyperglycaemic conditions, resulting in the delay of bone healing.
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Affiliation(s)
- Hitomi Fujikawa
- Department of Orthopaedic Surgery, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, 520-2192, Shiga, Japan.
| | - Hideto Kojima
- Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, 520-2192, Shiga, Japan
| | - Tomoya Terashima
- Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, 520-2192, Shiga, Japan
| | - Miwako Katagi
- Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, 520-2192, Shiga, Japan
| | - Takafumi Yayama
- Department of Orthopaedic Surgery, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, 520-2192, Shiga, Japan
| | - Kosuke Kumagai
- Department of Orthopaedic Surgery, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, 520-2192, Shiga, Japan
| | - Kanji Mori
- Department of Orthopaedic Surgery, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, 520-2192, Shiga, Japan.
| | - Hideki Saito
- Department of Orthopaedic Surgery, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, 520-2192, Shiga, Japan
| | - Shinji Imai
- Department of Orthopaedic Surgery, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, 520-2192, Shiga, Japan
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Kojima H, Katagi M, Okano J, Nakae Y, Ohashi N, Fujino K, Miyazawa I, Nakagawa T. Complete remission of diabetes with a transient HDAC inhibitor and insulin in streptozotocin mice. Commun Biol 2023; 6:637. [PMID: 37311905 DOI: 10.1038/s42003-023-05010-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 06/02/2023] [Indexed: 06/15/2023] Open
Abstract
Despite the growing epidemic worldwide, diabetes is an incurable disease. We have been focusing on why diabetes manifests refractoriness to any therapy. We recently found that abnormal bone marrow-derived cells (BMDCs), namely, Vcam-1+ST-HSCs, was a key mechanism for diabetic complications. We then hypothesize that those aberrant BMDCs sustainedly impair pancreatic β cells. Here we show that eliminating abnormal BMDCs using bone marrow transplantation results in controlling serum glucose in diabetic mice, in which normoglycemia is sustained even after cessation of insulin therapy. Alternatively, abnormal BMDCs exhibiting epigenetic alterations are treated with an HDAC inhibitor, givinostat, in diabetic mice. As a result, those mice are normoglycemic along with restored insulin secretion even following the cessation of both insulin and givinostat. Diabetic cell fusion between abnormal BMDCs and resident cells is significantly blocked by the combination therapy in the pancreatic islets and thymus while surgical ablation of the thymus completely eliminates therapeutic protection in diabetic mice. In conclusion, diabetes is an epigenetic stem cell disorder with thymic disturbances. The combination may be applied to patients aiming at complete remission from diabetes in clinical medicine.
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Grants
- No. 18390100 Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- No. 023590378 Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- No. 16K19051 Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- No. 16K15756 Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- No.1515503ZZE Shiga University of Medical Science (SUMS)
- No. 1515503 W Shiga University of Medical Science (SUMS)
- No. 1515503ZE Shiga University of Medical Science (SUMS)
- No. 1515503ZB Shiga University of Medical Science (SUMS)
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Affiliation(s)
- Hideto Kojima
- Department of Biocommunication Development, Shiga University of Medical Science, Otsu, Japan.
- Department of Regenerative Medicine Development, Shiga University of Medical Science, Otsu, Japan.
| | - Miwako Katagi
- Department of Biocommunication Development, Shiga University of Medical Science, Otsu, Japan
| | - Junko Okano
- Department of Plastic and Reconstructive Surgery, Shiga University of Medical Science, Otsu, Japan
| | - Yuki Nakae
- Department of Regenerative Medicine Development, Shiga University of Medical Science, Otsu, Japan
| | - Natsuko Ohashi
- Department of Medicine, Division of Diabetology, Endocrinology and Nephrology, Shiga University of Medical Science, Otsu, Japan
| | - Kazunori Fujino
- Department of Critical and Intensive Care Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Itsuko Miyazawa
- Department of Education Center for Medicine and Nursing, Shiga University of Medical Science, Otsu, Japan
| | - Takahiko Nakagawa
- Department of Biocommunication Development, Shiga University of Medical Science, Otsu, Japan.
- Department of Regenerative Medicine Development, Shiga University of Medical Science, Otsu, Japan.
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Memetimin H, Zhu B, Lee S, Katz WS, Kern PA, Finlin BS. Improved β-cell function leads to improved glucose tolerance in a transgenic mouse expressing lipoprotein lipase in adipocytes. Sci Rep 2022; 12:22291. [PMID: 36566329 PMCID: PMC9789969 DOI: 10.1038/s41598-022-26995-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 12/22/2022] [Indexed: 12/25/2022] Open
Abstract
Lipoprotein lipase (LPL) hydrolyzes the triglyceride core of lipoproteins and also functions as a bridge, allowing for lipoprotein and cholesterol uptake. Transgenic mice expressing LPL in adipose tissue under the control of the adiponectin promoter (AdipoQ-LPL) have improved glucose metabolism when challenged with a high fat diet. Here, we studied the transcriptional response of the adipose tissue of these mice to acute high fat diet exposure. Gene set enrichment analysis (GSEA) provided mechanistic insight into the improved metabolic phenotype of AdipoQ-LPL mice. First, the cholesterol homeostasis pathway, which is controlled by the SREBP2 transcription factor, is repressed in gonadal adipose tissue AdipoQ-LPL mice. Furthermore, we identified SND1 as a link between SREBP2 and CCL19, an inflammatory chemokine that is reduced in AdipoQ-LPL mice. Second, GSEA identified a signature for pancreatic β-cells in adipose tissue of AdipoQ-LPL mice, an unexpected finding. We explored whether β-cell function is improved in AdipoQ-LPL mice and found that the first phase of insulin secretion is increased in mice challenged with high fat diet. In summary, we identify two different mechanisms for the improved metabolic phenotype of AdipoQ-LPL mice. One involves improved adipose tissue function and the other involves adipose tissue-pancreatic β-cell crosstalk.
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Affiliation(s)
- Hasiyet Memetimin
- grid.266539.d0000 0004 1936 8438Division of Endocrinology, and the Barnstable Brown Diabetes and Obesity Center, Department of Medicine, University of Kentucky, Lexington, KY USA
| | - Beibei Zhu
- grid.266539.d0000 0004 1936 8438Division of Endocrinology, and the Barnstable Brown Diabetes and Obesity Center, Department of Medicine, University of Kentucky, Lexington, KY USA
| | - Sangderk Lee
- grid.266539.d0000 0004 1936 8438Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY USA
| | - Wendy S. Katz
- grid.266539.d0000 0004 1936 8438Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY USA
| | - Philip A. Kern
- grid.266539.d0000 0004 1936 8438Division of Endocrinology, and the Barnstable Brown Diabetes and Obesity Center, Department of Medicine, University of Kentucky, Lexington, KY USA
| | - Brian S. Finlin
- grid.266539.d0000 0004 1936 8438Division of Endocrinology, and the Barnstable Brown Diabetes and Obesity Center, Department of Medicine, University of Kentucky, Lexington, KY USA
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Miljkovic I, Cvejkus R, An P, Thyagarajan B, Christensen K, Wojczynski M, Schupf N, Zmuda JM. Low Risk for Developing Diabetes Among the Offspring of Individuals With Exceptional Longevity and Their Spouses. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2022; 3:753986. [PMID: 36992755 PMCID: PMC10012150 DOI: 10.3389/fcdhc.2022.753986] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 03/15/2022] [Indexed: 11/13/2022]
Abstract
Little is known about the risk of type 2 diabetes (T2D) among the offspring of individuals with exceptional longevity. We determined the incidence of and potential risk and protective factors for T2D among the offspring of probands and offspring’s spouses (mean age=60 years, range 32-88 years) in the Long Life Family Study (LLFS), a multicenter cohort study of 583 two-generation families with a clustering of healthy aging and exceptional longevity. Incident T2D was defined as fasting serum glucose ≥126 mg/dl, or HbA1c of ≥6.5%, or self-reported with doctor diagnosis of T2D, or the use of anti-diabetic medication during a mean follow-up 7.9 ± 1.1 years. Among offspring (n=1105) and spouses (n=328) aged 45-64 years without T2D at baseline visit, the annual incident rate of T2D was 3.6 and 3.0 per 1000 person-years, respectively, while among offspring (n=444) and spouses (n=153) aged 65+ years without T2D at baseline, the annual incident rate of T2D was 7.2 and 7.4 per 1000 person-years, respectively. By comparison, the annual incident rate of T2D per 1000 person-years in the U.S. general population was 9.9 among those aged 45-64, and 8.8 among those aged 65+ years (2018 National Health Interview Survey). Baseline BMI, waist circumference, and fasting serum triglycerides were positively associated with incident T2D, whereas fasting serum HDL-C, adiponectin, and sex hormone binding globulin were protective against incident T2D among the offspring (all P<0.05). Similar associations were observed among their spouses (all P<0.05, except sex hormone binding globulin). In addition, we observed that among spouses, but not offspring, fasting serum interleukin 6 and insulin-like growth factor 1 were positively associated with incident T2D (P<0.05 for both). Our study suggests that both offspring of long-living individuals and their spouses, especially middle-aged, share a similar low risk for developing T2D as compared with the general population. Our findings also raise the possibility that distinct biological risk and protective factors may contribute to T2D risk among offspring of long-lived individuals when compared with their spouses. Future studies are needed to identify the mechanisms underlying low T2D risk among the offspring of individuals with exceptional longevity, and also among their spouses.
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Affiliation(s)
- Iva Miljkovic
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
- *Correspondence: Iva Miljkovic,
| | - Ryan Cvejkus
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
| | - Ping An
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
| | - Bharat Thyagarajan
- Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Kaare Christensen
- Department of Epidemiology, Biostatistics and Biodemography, Danish Aging Research Center, University of Southern Denmark, Odense, Denmark
| | - Mary Wojczynski
- Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
| | - Nicole Schupf
- Taub Institute, Columbia University, New York, NY, United States
| | - Joseph M. Zmuda
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
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Ma Z, Liu R, Cao F, Li J, Yang J, Kang K, Gao Z, Zhao D. Bone screws of porous silicon carbide coated with tantalum improve osseointegration and osteogenesis in goat femoral neck fractures. Biomed Mater 2021; 16. [PMID: 34192669 DOI: 10.1088/1748-605x/ac103b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 06/30/2021] [Indexed: 11/11/2022]
Abstract
Traditional metal materials, such as stainless steel and titanium (Ti) alloys, are still the gold standards for fracture fixation. However, the elastic moduli of these materials differ from that of human cortical bone, and the stress shielding effect affects fracture healing, leading to secondary fractures. Herein, a new porous Ta coated SiC (pTa-SiC) scaffold using in internal fixation devices with good mechanical and biological properties was prepared based on porous silicon carbide (SiC) scaffold and tantalum (Ta) metal. The osteogenic and osseointegration properties of the pTa-SiC scaffold were investigated by bothin vitroandin vivotests. The results showed that compared with porous titanium (pTi), the pTa-SiC promoted the proliferation, migration, and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. Moreover, the internal fixation tests were carried out in a goat load-bearing femoral neck fracture model. Histological results showed good osseointegration around the pTa-SiC screws. And the acid etching results showed that bone cells grew tightly on the pTa-SiC throughout bone canaliculi, and the growth mode was contact osteogenesis, which indicated good biological fixation effects. Therefore, it is reasonable to be expected that the new pTa-SiC scaffold with excellent mechanical and biological properties could be a promising candidate for bone implant field.
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Affiliation(s)
- Zhijie Ma
- School of Biomedical Engineering, Dalian University of Technology, Dalian 116024, People's Republic of China
| | - Rong Liu
- School of Biomedical Engineering, Dalian University of Technology, Dalian 116024, People's Republic of China
| | - Fang Cao
- School of Biomedical Engineering, Dalian University of Technology, Dalian 116024, People's Republic of China
| | - Jingyu Li
- Orthopaedic of Department, Affiliated ZhongShan Hospital of Dalian University, Dalian 116001, People's Republic of China
| | - Jiahui Yang
- Orthopaedic of Department, Affiliated ZhongShan Hospital of Dalian University, Dalian 116001, People's Republic of China
| | - Kai Kang
- Orthopaedic of Department, Affiliated ZhongShan Hospital of Dalian University, Dalian 116001, People's Republic of China
| | - Ziqi Gao
- Orthopaedic of Department, Affiliated ZhongShan Hospital of Dalian University, Dalian 116001, People's Republic of China
| | - Dewei Zhao
- Orthopaedic of Department, Affiliated ZhongShan Hospital of Dalian University, Dalian 116001, People's Republic of China
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Baikenova MB, Chereshnev VA, Sokolova KV, Gette IF, Emelyanov VV, Danilova IG. Hepatic Insulin-Positive Cells and Major Transcription Factors (PDX1, MAFA, NGN3) in Rat Models of Type 1 and Type 2 Diabetes Mellitus. J EVOL BIOCHEM PHYS+ 2021. [DOI: 10.1134/s0022093021040037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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11
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Malfunctioning CD106-positive, short-term hematopoietic stem cells trigger diabetic neuropathy in mice by cell fusion. Commun Biol 2021; 4:575. [PMID: 33990693 PMCID: PMC8121918 DOI: 10.1038/s42003-021-02082-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 03/25/2021] [Indexed: 12/16/2022] Open
Abstract
Diabetic neuropathy is an incurable disease. We previously identified a mechanism by which aberrant bone marrow-derived cells (BMDCs) pathologically expressing proinsulin/TNF-α fuse with residential neurons to impair neuronal function. Here, we show that CD106-positive cells represent a significant fraction of short-term hematopoietic stem cells (ST-HSCs) that contribute to the development of diabetic neuropathy in mice. The important role for these cells is supported by the fact that transplantation of either whole HSCs or CD106-positive ST-HSCs from diabetic mice to non-diabetic mice produces diabetic neuronal dysfunction in the recipient mice via cell fusion. Furthermore, we show that transient episodic hyperglycemia produced by glucose injections leads to abnormal fusion of pathological ST-HSCs with residential neurons, reproducing neuropathy in nondiabetic mice. In conclusion, we have identified hyperglycemia-induced aberrant CD106-positive ST-HSCs underlie the development of diabetic neuropathy. Aberrant CD106-positive ST-HSCs constitute a novel therapeutic target for the treatment of diabetic neuropathy. Katagi et al. show that abnormal bone marrow-derived cells originated from hematopoietic stem cells (CD106-positive short-term HSCs) aberrantly fuse with neurons to develop diabetic neuropathy. This study suggests that the pathological abnormality is memorized in the bone marrow and that it cannot be erased by conventional therapy.
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Kh S, Haider KH. Stem Cells: A Renewable Source of Pancreatic β-Cells and Future for Diabetes Treatment. Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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13
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Binenbaum I, Atamni HAT, Fotakis G, Kontogianni G, Koutsandreas T, Pilalis E, Mott R, Himmelbauer H, Iraqi FA, Chatziioannou AA. Container-aided integrative QTL and RNA-seq analysis of Collaborative Cross mice supports distinct sex-oriented molecular modes of response in obesity. BMC Genomics 2020; 21:761. [PMID: 33143653 PMCID: PMC7640698 DOI: 10.1186/s12864-020-07173-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 10/21/2020] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND The Collaborative Cross (CC) mouse population is a valuable resource to study the genetic basis of complex traits, such as obesity. Although the development of obesity is influenced by environmental factors, underlying genetic mechanisms play a crucial role in the response to these factors. The interplay between the genetic background and the gene expression pattern can provide further insight into this response, but we lack robust and easily reproducible workflows to integrate genomic and transcriptomic information in the CC mouse population. RESULTS We established an automated and reproducible integrative workflow to analyse complex traits in the CC mouse genetic reference panel at the genomic and transcriptomic levels. We implemented the analytical workflow to assess the underlying genetic mechanisms of host susceptibility to diet induced obesity and integrated these results with diet induced changes in the hepatic gene expression of susceptible and resistant mice. Hepatic gene expression differs significantly between obese and non-obese mice, with a significant sex effect, where male and female mice exhibit different responses and coping mechanisms. CONCLUSION Integration of the data showed that different genes but similar pathways are involved in the genetic susceptibility and disturbed in diet induced obesity. Genetic mechanisms underlying susceptibility to high-fat diet induced obesity are different in female and male mice. The clear distinction we observed in the systemic response to the high-fat diet challenge and to obesity between male and female mice points to the need for further research into distinct sex-related mechanisms in metabolic disease.
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Affiliation(s)
- Ilona Binenbaum
- Division of Pediatric Hematology-Oncology, First Department of Pediatrics, National and Kapodistrian University of Athens, Athens, Greece
- Department of Biology, University of Patras, Patras, Greece
| | - Hanifa Abu-Toamih Atamni
- Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Georgios Fotakis
- Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
- e-NIOS PC, Kallithea, Athens, Greece
| | - Georgia Kontogianni
- Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Theodoros Koutsandreas
- e-NIOS PC, Kallithea, Athens, Greece
- Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Eleftherios Pilalis
- e-NIOS PC, Kallithea, Athens, Greece
- Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Richard Mott
- Department of Genetics, University College of London, London, UK
| | - Heinz Himmelbauer
- Institute of Computational Biology, Department of Biotechnology, University of Life Sciences and Natural Resources, Vienna (BOKU), Vienna, Austria
- Centre for Genomic Regulation (CRG), Barcelona, Spain
| | - Fuad A Iraqi
- Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
| | - Aristotelis A Chatziioannou
- e-NIOS PC, Kallithea, Athens, Greece.
- Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
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14
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Ramzy A, Tudurí E, Glavas MM, Baker RK, Mojibian M, Fox JK, O'Dwyer SM, Dai D, Hu X, Denroche HC, Edeer N, Gray SL, Verchere CB, Johnson JD, Kieffer TJ. AAV8 Ins1-Cre can produce efficient β-cell recombination but requires consideration of off-target effects. Sci Rep 2020; 10:10518. [PMID: 32601405 PMCID: PMC7324556 DOI: 10.1038/s41598-020-67136-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 06/03/2020] [Indexed: 12/11/2022] Open
Abstract
In vivo genetic manipulation is used to study the impact of gene deletion or re-expression on β-cell function and organism physiology. Cre-LoxP is a system wherein LoxP sites flanking a gene are recognized by Cre recombinase. Cre transgenic mice are the most prevalent technology used to deliver Cre but many models have caveats of off-target recombination, impaired β-cell function, and high cost of animal production. Inducible estrogen receptor conjugated Cre models face leaky recombination and confounding effects of tamoxifen. As an alternative, we characterize an adeno associated virus (AAV) with a rat insulin 1 promoter driving Cre recombinase (AAV8 Ins1-Cre) that is economical and rapid to implement, and has limited caveats. Intraperitoneal AAV8 Ins1-Cre produced efficient β-cell recombination, alongside some hepatic, exocrine pancreas, α-cell, δ-cell, and hypothalamic recombination. Delivery of lower doses via the pancreatic duct retained good rates of β-cell recombination and limited rates of off-target recombination. Unlike inducible Cre in transgenic mice, AAV8 Ins1-Cre required no tamoxifen and premature recombination was avoided. We demonstrate the utility of this technology by inducing hyperglycemia in inducible insulin knockout mice (Ins1−/−;Ins2f/f). AAV-mediated expression of Cre in β-cells provides an effective alternative to transgenic approaches for inducible knockout studies.
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Affiliation(s)
- Adam Ramzy
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Eva Tudurí
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.,Instituto de Investigación, Desarrollo e innovación en Biotecnología Sanitaria de Elche (IDiBE), Elche, Spain
| | - Maria M Glavas
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Robert K Baker
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Majid Mojibian
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jessica K Fox
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Shannon M O'Dwyer
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Derek Dai
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Xiaoke Hu
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Heather C Denroche
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Nazde Edeer
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Sarah L Gray
- Northern Medical Program, University of Northern British Columbia, Prince George, British Columbia, Canada
| | - Cameron B Verchere
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Pathology and Laboratory Medicine, BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - James D Johnson
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Timothy J Kieffer
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada. .,Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
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15
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Addison P, Fatakhova K, Rodriguez Rilo HL. Considerations for an Alternative Site of Islet Cell Transplantation. J Diabetes Sci Technol 2020; 14:338-344. [PMID: 31394934 PMCID: PMC7196852 DOI: 10.1177/1932296819868495] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Islet cell transplantation has been limited most by poor graft survival. Optimizing the site of transplantation could improve clinical outcomes by minimizing required donor cells, increasing graft integration, and simplifying the transplantation and monitoring process. In this article, we review the history and significant human and animal data for clinically relevant sites, including the liver, spleen, and kidney subcapsule, and identify promising new sites for further research. While the liver was the first studied site and has been used the most in clinical practice, the majority of transplanted islets become necrotic. We review the potential causes for graft death, including the instant blood-mediated inflammatory reaction, exposure to immunosuppressive agents, and low oxygen tension. Significant research exists on alternative sites for islet cell transplantation, suggesting a promising future for patients undergoing pancreatectomy.
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Affiliation(s)
- Poppy Addison
- Donald and Barbara Zucker School of
Medicine at Hofstra/Northwell, Hempstead, NY, USA
- Pancreas Disease Center, Northwell
Health System, Manhasset, NY, USA
| | - Karina Fatakhova
- Donald and Barbara Zucker School of
Medicine at Hofstra/Northwell, Hempstead, NY, USA
- Pancreas Disease Center, Northwell
Health System, Manhasset, NY, USA
| | - Horacio L. Rodriguez Rilo
- Donald and Barbara Zucker School of
Medicine at Hofstra/Northwell, Hempstead, NY, USA
- Pancreas Disease Center, Northwell
Health System, Manhasset, NY, USA
- Horacio L. Rodriguez Rilo, MD, Pancreas
Disease Center, 350 Lakeville Road, New Hyde Park, NY 11042, USA.
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16
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Pardridge WM. Blood-Brain Barrier and Delivery of Protein and Gene Therapeutics to Brain. Front Aging Neurosci 2020; 11:373. [PMID: 31998120 PMCID: PMC6966240 DOI: 10.3389/fnagi.2019.00373] [Citation(s) in RCA: 226] [Impact Index Per Article: 45.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 12/19/2019] [Indexed: 01/02/2023] Open
Abstract
Alzheimer’s disease (AD) and treatment of the brain in aging require the development of new biologic drugs, such as recombinant proteins or gene therapies. Biologics are large molecule therapeutics that do not cross the blood-brain barrier (BBB). BBB drug delivery is the limiting factor in the future development of new therapeutics for the brain. The delivery of recombinant protein or gene medicines to the brain is a binary process: either the brain drug developer re-engineers the biologic with BBB drug delivery technology, or goes forward with brain drug development in the absence of a BBB delivery platform. The presence of BBB delivery technology allows for engineering the therapeutic to enable entry into the brain across the BBB from blood. Brain drug development may still take place in the absence of BBB delivery technology, but with a reliance on approaches that have rarely led to FDA approval, e.g., CSF injection, stem cells, small molecules, and others. CSF injection of drug is the most widely practiced approach to brain delivery that bypasses the BBB. However, drug injection into the CSF results in limited drug penetration to the brain parenchyma, owing to the rapid export of CSF from the brain to blood. A CSF injection of a drug is equivalent to a slow intravenous (IV) infusion of the pharmaceutical. Given the profound effect the existence of the BBB has on brain drug development, future drug or gene development for the brain will be accelerated by future advances in BBB delivery technology in parallel with new drug discovery.
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Affiliation(s)
- William M Pardridge
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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17
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Smith LIF, Hill TG, Bowe JE. Generating Beta-Cell-Specific Transgenic Mice Using the Cre-Lox System. Methods Mol Biol 2020; 2128:181-205. [PMID: 32180194 DOI: 10.1007/978-1-0716-0385-7_13] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Beta-cell-specific transgenic mice provide an invaluable model for dissecting the direct signaling mechanisms involved in regulating beta-cell structure and function. Furthermore, generating novel transgenic models is now easier and more cost-effective than ever, thanks to exciting novel approaches such as CRISPR.Here, we describe the commonly used approaches for generating and maintaining beta-cell-specific transgenic models and some of the considerations involved in their use. This includes the use of different beta-cell-specific promoters (e.g., pancreatic and duodenal homeobox factor 1 (Pdx1), rat insulin 2 promoter (RIP), and mouse insulin 1 promoter (MIP)) to drive site-specific recombinase technology. Important considerations during selection include level and uniformity of expression in the beta-cell population, ectopic transgene expression, and the use of inducible models.This chapter provides a guide to the procurement, generation, and maintenance of a beta-cell-specific transgene colony from preexisting Cre and loxP mouse strains, providing methods for crossbreeding and genotyping, as well as subsequent maintenance and, in the case of inducible models, transgenic induction.
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Affiliation(s)
- Lorna I F Smith
- Department of Diabetes, School of Life Course Sciences, King's College London, London, UK.
| | - Thomas G Hill
- Department of Diabetes, School of Life Course Sciences, King's College London, London, UK
| | - James E Bowe
- Department of Diabetes, School of Life Course Sciences, King's College London, London, UK
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18
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Barton M, Prossnitz ER. Early life stress determines insulin signalling in adulthood. J Physiol 2019; 598:427-428. [PMID: 31785103 DOI: 10.1113/jp279300] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Affiliation(s)
- Matthias Barton
- Molecular Internal Medicine, University of Zürich, Zürich.,Andreas Grüntzig Foundation, Zürich, Switzerland
| | - Eric R Prossnitz
- Division of Molecular Medicine, Department of Internal Medicine.,University of New Mexico Comprehensive Cancer Center.,Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
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19
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Abu-Toamih Atamni HJ, Kontogianni G, Binenbaum I, Mott R, Himmelbauer H, Lehrach H, Chatziioannou A, Iraqi FA. Hepatic gene expression variations in response to high-fat diet-induced impaired glucose tolerance using RNAseq analysis in collaborative cross mouse population. Mamm Genome 2019; 30:260-275. [PMID: 31650267 DOI: 10.1007/s00335-019-09816-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2019] [Accepted: 10/09/2019] [Indexed: 12/14/2022]
Abstract
Hepatic gene expression is known to differ between healthy and type 2 diabetes conditions. Identifying these variations will provide better knowledge to the development of gene-targeted therapies. The aim of this study is to assess diet-induced hepatic gene expression of susceptible versus resistant CC lines to T2D development. Next-generation RNA-sequencing was performed for 84 livers of diabetic and non-diabetic mice of 41 different CC lines (both sexes) following 12 weeks on high-fat diet (42% fat). Data analysis revealed significant variations of hepatic gene expression in diabetic versus non-diabetic mice with significant sex effect, where 601 genes were differentially expressed (DE) in overall population (males and females), 718 genes in female mice, and 599 genes in male mice. Top prioritized DE candidate genes were Lepr, Ins2, Mb, Ckm, Mrap2, and Ckmt2 for the overall population; for females-only group were Hdc, Serpina12, Socs1, Socs2, and Mb, while for males-only group were Serpine1, Mb, Ren1, Slc4a1, and Atp2a1. Data analysis for sex differences revealed 193 DE genes in health (Top: Lepr, Cav1, Socs2, Abcg2, and Col5a3), and 389 genes DE between diabetic females versus males (Top: Lepr, Clps, Ins2, Cav1, and Mrap2). Furthermore, integrating gene expression results with previously published QTL, we identified significant variants mapped at chromosomes at positions 36-49 Mb, 62-71 Mb, and 79-99 Mb, on chromosomes 9, 11, and 12, respectively. Our findings emphasize the complexity of T2D development and that significantly controlled by host complex genetic factors. As well, we demonstrate the significant sex differences between males and females during health and increasing to extent levels during disease/diabetes. Altogether, opening the venue for further studies targets the discovery of effective sex-specific and personalized preventions and therapies.
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Affiliation(s)
- H J Abu-Toamih Atamni
- Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, 69978, Tel Aviv, Israel
| | - G Kontogianni
- Institute of Biology, Medicinal Chemistry & Biotechnology, National Hellenic Research Foundation, Athens, Greece
| | - I Binenbaum
- Institute of Biology, Medicinal Chemistry & Biotechnology, National Hellenic Research Foundation, Athens, Greece.,Department of Biology, University of Patras, Patras, Greece
| | - R Mott
- Department of Genetics, University College of London, London, UK
| | - H Himmelbauer
- Centre for Genomic Regulation (CRG), Barcelona, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain.,University of Natural Resources and Life Sciences (BOKU), Vienna, Austria
| | - H Lehrach
- Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - A Chatziioannou
- Institute of Biology, Medicinal Chemistry & Biotechnology, National Hellenic Research Foundation, Athens, Greece.,e-NIOS Applications PC, 17671, Kallithea, Greece
| | - Fuad A Iraqi
- Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, 69978, Tel Aviv, Israel.
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20
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Dou X, Wei X, Liu G, Wang S, Lv Y, Li J, Ma Z, Zheng G, Wang Y, Hu M, Yu W, Zhao D. Effect of porous tantalum on promoting the osteogenic differentiation of bone marrow mesenchymal stem cells in vitro through the MAPK/ERK signal pathway. J Orthop Translat 2019; 19:81-93. [PMID: 31844616 PMCID: PMC6896724 DOI: 10.1016/j.jot.2019.03.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 03/02/2019] [Accepted: 03/18/2019] [Indexed: 02/09/2023] Open
Abstract
BACKGROUND As an ideal new graft material, porous tantalum (pTa) has excellent mechanical properties and corrosion resistance and has received increased attention in the biomedical field because of its excellent cytocompatibility and ability to induce bone formation. However, the molecular mechanism of its potential to promote osteogenesis remains unclear, and very few reports have been published on this topic. METHODS In this study, we first produced porous Ti6Al4V (pTi6Al4V) and pTa with the same pore size by three-dimensional printing combined with chemical vapour deposition. The number of adhesions between pTa and pTi6Al4V and bone marrow mesenchymal stem cells (BMSCs) after 1 day of culture was detected by the live/dead cell staining method. The proliferation activity of the two groups was determined after culture for 1, 3, 5 and 7 days by the cell counting kit-8 method. In addition, the osteogenic activity, mRNA expression levels of osteogenic genes alkaline phosphatase (ALP), osterix (OSX), collagen-I (Col-I), osteonectin (OSN) and osteocalcin (OCN) and protein expression levels of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signalling pathway marker p-ERK of the two groups cultured for 7, 14 and 21 days were determined by the ALP activity assay, real-time quantitative polymerase chain reaction (Q-PCR) and Western blotting, respectively. Subsequently, the two groups were treated with the MAPK/ERK-specific inhibitor U0126, and then, the mRNA expression levels of osteogenic genes and protein expression levels of p-ERK in the cultures were determined by Q-PCR and Western blotting, respectively. RESULTS The live/dead cell staining and cell counting kit-8 assays showed that the adhesion and proliferation activities of BMSCs on pTa were significantly better than those on pTi6Al4V. In addition, the ALP activity assay and Q-PCR showed that pTa harboured osteogenic activity and that the osteogenic genes ALP, OSX, Col-I, OSN and OCN were highly expressed, and by Western blotting, the expression of p-ERK protein in the pTa group was also significantly higher than that in the pTi6Al4V group. Subsequently, using the MAPK/ERK-specific inhibitor U0126, Western blotting showed that the expression of p-ERK protein was significantly inhibited and that there was no difference between the two groups. Furthermore, Q-PCR showed that osteogenic gene expression and ALP expression levels were significantly increased in the pTa group, and there were no differences in the OSX, Col-I, OSN and OCN mRNA expression levels between the two groups. CONCLUSION Overall, our research found that compared with the widely used titanium alloy materials, our pTa can promote the adhesion and proliferation of BMSCs, and the molecular mechanism of pTa may occur via activation of the MAPK/ERK signalling pathway to regulate the high expression of OSX, Col I, OSN and OCN osteogenic genes and promote the osteogenic differentiation of BMSCs in vitro. The translational potential of this article : Our self-developed pTa material produced by three-dimensional printing combined with the chemical vapour deposition method not only retains excellent biological activity and osteoinductive ability of the original tantalum metal but also saves considerably on material costs to achieve mass production of personalised orthopaedic implants with pTa as a stent and to accelerate the wide application of pTa implants in clinical practice, which have certain profound significance.
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Affiliation(s)
- Xiaojie Dou
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Xiaowei Wei
- Laboratory of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Ge Liu
- Laboratory of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Shuai Wang
- Department of Orthopedics, Binzhou People's Hospital, Binzhou, Shandong, China
| | - Yongxiang Lv
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Junlei Li
- Laboratory of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Zhijie Ma
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Guoshuang Zheng
- Laboratory of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Yikai Wang
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Minghui Hu
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Weiting Yu
- Laboratory of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
| | - Dewei Zhao
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China
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21
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Magdaleno F, Blajszczak CC, Charles-Niño CL, Guadrón-Llanos AM, Vázquez-Álvarez AO, Miranda-Díaz AG, Nieto N, Islas-Carbajal MC, Rincón-Sánchez AR. Aminoguanidine reduces diabetes-associated cardiac fibrosis. Exp Ther Med 2019; 18:3125-3138. [PMID: 31572553 DOI: 10.3892/etm.2019.7921] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 05/31/2019] [Indexed: 02/07/2023] Open
Abstract
Aminoguanidine (AG) inhibits advanced glycation end products (AGEs) and advanced oxidation protein products (AOPP) accumulated as a result of excessive oxidative stress in diabetes. However, the molecular mechanism by which AG reduces AGE-associated damage in diabetes is not well understood. Thus, we investigated whether AG supplementation mitigates oxidative-associated cardiac fibrosis in rats with type 2 diabetes mellitus (T2DM). Forty-five male Wistar rats were divided into three groups: Control, T2DM and T2DM+AG. Rats were fed with a high-fat, high-carbohydrate diet (HFCD) for 2 weeks and rendered diabetic using low-dose streptozotocin (STZ) (20 mg/kg), and one group was treated with AG (20 mg/kg) up to 25 weeks. In vitro experiments were performed in primary rat myofibroblasts to confirm the antioxidant and antifibrotic effects of AG and to determine if blocking the receptor for AGEs (RAGE) prevents the fibrogenic response in myofibroblasts. Diabetic rats exhibited an increase in cardiac fibrosis resulting from HFCD and STZ injections. By contrast, AG treatment significantly reduced cardiac fibrosis, α-smooth muscle actin (αSMA) and oxidative-associated Nox4 and Nos2 mRNA expression. In vitro challenge of myofibroblasts with AG under T2DM conditions reduced intra- and extracellular collagen type I expression and Pdgfb, Tgfβ1 and Col1a1 mRNAs, albeit with similar expression of Tnfα and Il6 mRNAs. This was accompanied by reduced phosphorylation of ERK1/2 and SMAD2/3 but not of AKT1/2/3 and STAT pathways. RAGE blockade further attenuated collagen type I expression in AG-treated myofibroblasts. Thus, AG reduces oxidative stress-associated cardiac fibrosis by reducing pERK1/2, pSMAD2/3 and collagen type I expression via AGE/RAGE signaling in T2DM.
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Affiliation(s)
- Fernando Magdaleno
- Department of Physiology, University Center of Health Sciences, Guadalajara University, Guadalajara, Jalisco 44340, Mexico.,Department of Pathology, College of Medicine, University of Illinois at Chicago, IL 60612, USA
| | | | - Claudia Lisette Charles-Niño
- Department of Physiology, University Center of Health Sciences, Guadalajara University, Guadalajara, Jalisco 44340, Mexico.,Department of Microbiology and Pathology, University Center of Health Sciences, Guadalajara University, Guadalajara, Jalisco 44340, Mexico
| | - Alma Marlene Guadrón-Llanos
- Department of Physiology, University Center of Health Sciences, Guadalajara University, Guadalajara, Jalisco 44340, Mexico
| | - Alan Omar Vázquez-Álvarez
- Department of Physiology, University Center of Health Sciences, Guadalajara University, Guadalajara, Jalisco 44340, Mexico
| | - Alejandra Guillermina Miranda-Díaz
- Institute of Experimental and Clinical Therapeutics, Department of Physiology, University Center of Health Sciences, Guadalajara University, Guadalajara, Jalisco 44340, Mexico
| | - Natalia Nieto
- Department of Pathology, College of Medicine, University of Illinois at Chicago, IL 60612, USA
| | - María Cristina Islas-Carbajal
- Institute of Experimental and Clinical Therapeutics, Department of Physiology, University Center of Health Sciences, Guadalajara University, Guadalajara, Jalisco 44340, Mexico
| | - Ana Rosa Rincón-Sánchez
- Institute of Molecular Biology and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, Guadalajara University, Guadalajara, Jalisco 44340, Mexico
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22
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Martin JH, Aitken RJ, Bromfield EG, Cafe SL, Sutherland JM, Frost ER, Nixon B, Lord T. Investigation into the presence and functional significance of proinsulin C-peptide in the female germline†. Biol Reprod 2019; 100:1275-1289. [PMID: 30715203 DOI: 10.1093/biolre/ioz008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2018] [Revised: 12/10/2018] [Accepted: 01/28/2019] [Indexed: 08/02/2024] Open
Abstract
Diabetes is associated with poor oocyte quality and the dysregulation of ovarian function and is thus a leading contributor to the increasing prevalence of female reproductive pathologies. Accordingly, it is well-established that insulin fulfills a key role in the regulation of several facets of female reproduction. What remains less certain is whether proinsulin C-peptide, which has recently been implicated in cellular signaling cascades, holds a functional role in the female germline. In the present study, we examined the expression of insulin, C-peptide, and its purported receptor; GPR146, within the mouse ovary and oocyte. Our data establish the presence of abundant C-peptide within follicular fluid and raise the prospect that this bioactive peptide is internalized by oocytes in a G-protein coupled receptor-dependent manner. Further, our data reveal that internalized C-peptide undergoes pronounced subcellular relocalization from the ooplasm to the pronuclei postfertilization. The application of immunoprecipitation analysis and mass spectrometry identified breast cancer type 2 susceptibility protein (BRCA2), the meiotic resumption/DNA repair protein, as a primary binding partner for C-peptide within the oocyte. Collectively, these findings establish a novel accumulation profile for C-peptide in the female germline and provide the first evidence for an interaction between C-peptide and BRCA2. This interaction is particularly intriguing when considering the propensity for oocytes from diabetic women to experience aberrant meiotic resumption and perturbation of traditional DNA repair processes. This therefore provides a clear imperative for further investigation of the implications of dysregulated C-peptide production in these individuals.
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Affiliation(s)
- Jacinta H Martin
- Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The Hunter Medical Research Institute, New Lambton Heights and the University of Newcastle, Callaghan, Newcastle, Australia
| | - R John Aitken
- Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The Hunter Medical Research Institute, New Lambton Heights and the University of Newcastle, Callaghan, Newcastle, Australia
| | - Elizabeth G Bromfield
- Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The Hunter Medical Research Institute, New Lambton Heights and the University of Newcastle, Callaghan, Newcastle, Australia
| | - Shenae L Cafe
- Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The Hunter Medical Research Institute, New Lambton Heights and the University of Newcastle, Callaghan, Newcastle, Australia
| | - Jessie M Sutherland
- Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The Hunter Medical Research Institute, New Lambton Heights and the University of Newcastle, Callaghan, Newcastle, Australia
| | - Emily R Frost
- Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The Hunter Medical Research Institute, New Lambton Heights and the University of Newcastle, Callaghan, Newcastle, Australia
| | - Brett Nixon
- Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The Hunter Medical Research Institute, New Lambton Heights and the University of Newcastle, Callaghan, Newcastle, Australia
| | - Tessa Lord
- Priority Research Centre for Reproductive Science, Discipline of Biological Sciences, The Hunter Medical Research Institute, New Lambton Heights and the University of Newcastle, Callaghan, Newcastle, Australia
- School of Molecular Biosciences, Centre for Reproductive Biology, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA
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23
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Oh JE, Choi OK, Park HS, Jung HS, Ryu SJ, Lee YD, Lee SA, Chung SS, Choi EY, Lee DS, Gho YS, Lee H, Park KS. Direct differentiation of bone marrow mononucleated cells into insulin producing cells using pancreatic β-cell-derived components. Sci Rep 2019; 9:5343. [PMID: 30926860 PMCID: PMC6441031 DOI: 10.1038/s41598-019-41823-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 03/04/2019] [Indexed: 12/31/2022] Open
Abstract
Transplantation of stem cell-derived insulin producing cells (IPCs) has been proposed as an alternative to islet transplantation for the treatment of diabetes mellitus. However, current IPC differentiation protocols are focused on generating functional cells from the pluripotent stem cells and tend to rely on multistep, long-term exposure to various exogenous factors. In this study, we addressed the observation that under stress, pancreatic β-cells release essential components that direct the differentiation of the bone marrow nucleated cells (BMNCs) into IPCs. Without any supplementation with known differentiation-inducing factors, IPCs can be generated from BMNCs by in vitro priming for 6 days with conditioned media (CM) from the β-cells. In vitro primed BMNCs expressed the β-cell-specific transcription factors, as well as insulin, and improved hyperglycemia and glucose intolerance after transplantation into the streptozotocin-induced diabetic mice. Furthermore, we have found that components of the CM which trigger the differentiation were enclosed by or integrated into micro particles (MPs), rather than being secreted as soluble factors. Identification of these differentiation-directing factors might enable us to develop novel technologies required for the production of clinically applicable IPCs.
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Affiliation(s)
- Ju Eun Oh
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea.,Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 03080, Republic of Korea
| | - Ok Kyung Choi
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Ho Seon Park
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Hye Seung Jung
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Su Jeong Ryu
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Yong Deok Lee
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Seung-Ah Lee
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 03080, Republic of Korea
| | - Sung Soo Chung
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Eun Young Choi
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Dong-Sup Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Yong Song Gho
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, 37673, Republic of Korea
| | - Hakmo Lee
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea. .,Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, 05368, Republic of Korea.
| | - Kyong Soo Park
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Republic of Korea. .,Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 03080, Republic of Korea. .,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
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24
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Nobuta H, Katagi M, Kume S, Terashima T, Araki SI, Maegawa H, Kojima H, Nakagawa T. A role for bone marrow-derived cells in diabetic nephropathy. FASEB J 2018; 33:4067-4076. [PMID: 30496699 DOI: 10.1096/fj.201801825r] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Diabetes mellitus causes systemic disorders. We previously demonstrated that diabetic condition forced bone marrow-derived cells (BMDCs) to express TNF-α, leading to the development of diabetic neuropathy in mice. Here, we hypothesized that these abnormal BMDCs are also involved in diabetic nephropathy. To test our hypothesis, mice were irradiated to receive total bone marrow (BM) from the transgenic mice expressing green fluorescent protein before diabetes was induced by streptozotocin. Confocal microscopy showed that the diabetic glomerulus had more BMDCs compared with the nondiabetic glomerulus. Most of these cells exhibited endothelial phenotypes, being negative for several markers, including podocin (a maker of podocyte), α8 integrin (mesangial cell), CD68, and F4/80 (macrophage). Next, the total BM of diabetic mice was transplanted into nondiabetic mice to examine if diabetic BM per se could cause glomerular injury. The recipient mice exhibiting normal glycemia developed albuminuria and mesangial expansion with an increase in capillary area. The number of BMDCs increased in the glomerulus of the recipient mice. These cells were found to exhibit the endothelial phenotype and to express TNF-α. These data suggest that diabetic BMDCs per se could initiate glomerular disease. Finally, eNOS knockout mice were used to examine if residential endothelial injury could attract BMDCs into the glomerulus. However, endothelial dysfunction due to eNOS deficiency failed to attract BMDCs into the glomerulus. In summary, BMDCs may be involved in the development of diabetic nephropathy.-Nobuta, H., Katagi, M., Kume, S., Terashima, T., Araki, S., Maegawa, H., Kojima, H., Nakagawa, T. A role for bone marrow-derived cells in diabetic nephropathy.
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Affiliation(s)
- Hiroshi Nobuta
- Department of Medicine, Shiga University of Medical Science, Shiga, Japan.,Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Shiga, Japan; and
| | - Miwako Katagi
- Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Shiga, Japan; and
| | - Shinji Kume
- Department of Medicine, Shiga University of Medical Science, Shiga, Japan
| | - Tomoya Terashima
- Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Shiga, Japan; and
| | - Shin-Ichi Araki
- Department of Medicine, Shiga University of Medical Science, Shiga, Japan
| | - Hiroshi Maegawa
- Department of Medicine, Shiga University of Medical Science, Shiga, Japan
| | - Hideto Kojima
- Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Shiga, Japan; and
| | - Takahiko Nakagawa
- Department of Future Basic Medicine, Nara Medical University, Nara, Japan
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25
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Zhang H, Zhou Y, Zhang W, Wang K, Xu L, Ma H, Deng Y. Construction of vascularized tissue-engineered bone with a double-cell sheet complex. Acta Biomater 2018; 77:212-227. [PMID: 30017924 DOI: 10.1016/j.actbio.2018.07.024] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 06/25/2018] [Accepted: 07/10/2018] [Indexed: 12/14/2022]
Abstract
A double-cell sheet (DCS) complex composed of an osteogenic cell sheet and a vascular endothelial cell sheet with osteogenesis and blood vessel formation potential was developed in this study. The osteogenic and vascular endothelial cell sheets were obtained after induced culture of rabbit adipose-derived mesenchymal stem cells. The osteogenic cell sheet showed positive alizarin red, von Kossa, and alkaline phosphatase (ALP) staining. The vascular endothelial cell sheet exhibited visible W-P bodies in the cells, the expression of CD31 was positive, and a vascular mesh structure was spontaneously formed in a Matrigel matrix. The subcutaneous transplantation results for four groups of DCS and DCS-coral hydroxyapatite (CHA) complexes, and the CHA scaffold group in nude mice revealed mineralization of collagen fibers and vascularization in each group at 12 weeks, but the degrees of mineralization and vascularization showed differences among groups. The pattern involving endothelial cell sheets covered with osteogenic cell sheets, group B, exhibited the best results. In addition, the degree of mineralization of the DCS-CHA complexes was more mature than those of the same group of DCS complexes and the CHA scaffold, and the capillary number was greater than those of the same group of DCS complexes and the CHA scaffold. Therefore, the CHA scaffold strengthened the osteogenesis and blood vessel formation potential of the DCS complexes. Meanwhile, the DCS complexes also promoted the osteogenesis and blood vessel formation potential of the CHA scaffold. This study will provide a basis for building vascularized tissue-engineered bone for bone defect therapy. STATEMENT OF SIGNIFICANCE This study developed a double-cell sheet (DCS) complex composed of an osteogenic cell sheet and a vascular endothelial cell sheet with osteogenesis and blood vessel formation potential. Osteogenic and vascular endothelial cell sheets were obtained after induced culture of rabbit adipose-derived mesenchymal stem cells. The DCS complex and DCS-CHA complex exhibited osteogenic and blood vessel formation potential in vivo. CHA enhanced the osteogenesis and blood vessel formation abilities of the DCS complexes in vivo. Meanwhile, the DCS complexes also promoted the osteogenesis and blood vessel formation potential of the CHA scaffold. Group B of the DCS complexes and DCS-CHA complexes exhibited the best osteogenesis and blood vessel formation abilities.
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26
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Cedernaes J, Schönke M, Westholm JO, Mi J, Chibalin A, Voisin S, Osler M, Vogel H, Hörnaeus K, Dickson SL, Lind SB, Bergquist J, Schiöth HB, Zierath JR, Benedict C. Acute sleep loss results in tissue-specific alterations in genome-wide DNA methylation state and metabolic fuel utilization in humans. SCIENCE ADVANCES 2018; 4:eaar8590. [PMID: 30140739 PMCID: PMC6105229 DOI: 10.1126/sciadv.aar8590] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Accepted: 07/18/2018] [Indexed: 06/08/2023]
Abstract
Curtailed sleep promotes weight gain and loss of lean mass in humans, although the underlying molecular mechanisms are poorly understood. We investigated the genomic and physiological impact of acute sleep loss in peripheral tissues by obtaining adipose tissue and skeletal muscle after one night of sleep loss and after one full night of sleep. We find that acute sleep loss alters genome-wide DNA methylation in adipose tissue, and unbiased transcriptome-, protein-, and metabolite-level analyses also reveal highly tissue-specific changes that are partially reflected by altered metabolite levels in blood. We observe transcriptomic signatures of inflammation in both tissues following acute sleep loss, but changes involving the circadian clock are evident only in skeletal muscle, and we uncover molecular signatures suggestive of muscle breakdown that contrast with an anabolic adipose tissue signature. Our findings provide insight into how disruption of sleep and circadian rhythms may promote weight gain and sarcopenia.
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Affiliation(s)
| | - Milena Schönke
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Sweden
| | - Jakub Orzechowski Westholm
- Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Jia Mi
- Department of Chemistry–BMC, Uppsala University, Uppsala, Sweden
- Medicine and Pharmarcy Research Center, Binzhou Medical University, Yantai, China
| | - Alexander Chibalin
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Sweden
| | - Sarah Voisin
- Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Megan Osler
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Sweden
| | - Heike Vogel
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Potsdam, Germany
| | | | - Suzanne L. Dickson
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | | | - Jonas Bergquist
- Department of Chemistry–BMC, Uppsala University, Uppsala, Sweden
- Department of Pathology, University of Utah, Salt Lake City, UT 84132, USA
- Precision Medicine, Binzhou Medical University, Yantai, China
| | - Helgi B Schiöth
- Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Juleen R. Zierath
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Sweden
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27
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Sambataro M, Sambado L, Trevisiol E, Cacciatore M, Furlan A, Stefani PM, Seganfreddo E, Durante E, Conte S, Bella SD, Paccagnella A, Tos AP. Proinsulin‐expressing dendritic cells in type 2 neuropathic diabetic patients with and without foot lesions. FASEB J 2018; 32:3742-3751. [DOI: 10.1096/fj.201701279rr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Maria Sambataro
- Endocrine, Metabolism, and Nutrition Disease UnitDepartment of PathologyHematology UnitImmunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Luisa Sambado
- Endocrine, Metabolism, and Nutrition Disease UnitDepartment of PathologyHematology UnitImmunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Enrica Trevisiol
- Department of Pharmaceutical and Pharmacological SciencesUniversity of PaduaPaduaItaly
| | - Matilde Cacciatore
- Department of PathologyHematology UnitImmunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Anna Furlan
- Hematology UnitImmunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Piero Maria Stefani
- Hematology UnitImmunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Elena Seganfreddo
- Immunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Elisabetta Durante
- Immunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Stefania Conte
- Neurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Silvia Della Bella
- Department of Biomedical Technologies and Translational MedicineUniversity of MilanMilanItaly
- Laboratory of Clinical and Experimental ImmunologyHumanitas Clinical and Research CenterMilanItaly
| | - Agostino Paccagnella
- Endocrine, Metabolism, and Nutrition Disease UnitDepartment of PathologyHematology UnitImmunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Angelo Paolo Tos
- Department of PathologyHematology UnitImmunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
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28
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Tian P, Li B, He C, Song W, Hou A, Tian S, Meng X, Li K, Shan Y. Antidiabetic (type 2) effects of Lactobacillus G15 and Q14 in rats through regulation of intestinal permeability and microbiota. Food Funct 2018; 7:3789-3797. [PMID: 27713957 DOI: 10.1039/c6fo00831c] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The antidiabetic effects of Lactobacillus. paracasei subsp. paracasei G15 and Lactobacillus. casei Q14 in high fat diet and streptozotocin-induced type 2 diabetic (T2D) rats were evaluated in this study. The strains were separated from Chinese traditional fermented dairy food. Administration of G15 and Q14 for 6 weeks significantly improved the glucose tolerance and reduced the HbA1c levels in T2D rats. The probiotic treatment reduced the intestinal mucosal permeability and improved the epithelial barrier function through modification of the gut microbiota, which in turn lowered circulating LPS and inflammation cytokines, including IL-1β and IL-8, and eventually alleviated the inflammatory status and islet β-cell dysfunction. Combination of Q14 and metformin reversed the thymic atrophy and both G15 and Q14 lowered the circulating IL-6 level, indicating the immune-modulating potential of the strains. Lactobacillus. paracasei subsp. paracasei G15 and Lactobacillus. casei Q14 provide an insight into the biotherapy application of traditional fermented foods and their functional ingredients in the treatment of diabetes.
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Affiliation(s)
- Peijun Tian
- School of Food Science and Engineering, Harbin Institute of Technology, No. 73 Huanghe Road, Harbin 150000, China.
| | - Baolong Li
- Center of Safety and Evaluation of Drugs, Heilongjiang University of Chinese Medicine, No. 24 Heping Road, Harbin 150000, China
| | - Canxia He
- School of Food Science and Engineering, Harbin Institute of Technology, No. 73 Huanghe Road, Harbin 150000, China.
| | - Wei Song
- School of Food Science and Engineering, Harbin Institute of Technology, No. 73 Huanghe Road, Harbin 150000, China.
| | - Aiju Hou
- School of Food Science and Engineering, Harbin Institute of Technology, No. 73 Huanghe Road, Harbin 150000, China.
| | - Sicong Tian
- School of Food Science and Engineering, Harbin Institute of Technology, No. 73 Huanghe Road, Harbin 150000, China.
| | - Xinyu Meng
- Center of Safety and Evaluation of Drugs, Heilongjiang University of Chinese Medicine, No. 24 Heping Road, Harbin 150000, China
| | - Kaikai Li
- School of Food Science and Engineering, Harbin Institute of Technology, No. 73 Huanghe Road, Harbin 150000, China.
| | - Yujuan Shan
- School of Food Science and Engineering, Harbin Institute of Technology, No. 73 Huanghe Road, Harbin 150000, China.
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29
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Maldonado M, Huang T, Yang L, Xu L, Ma L. Human umbilical cord Wharton jelly cells promote extra-pancreatic insulin formation and repair of renal damage in STZ-induced diabetic mice. Cell Commun Signal 2017; 15:43. [PMID: 29041943 PMCID: PMC5645864 DOI: 10.1186/s12964-017-0199-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 10/05/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND We evaluated the therapeutic effect and fate of high doses of human umbilical cord Wharton jelly cells (hUCWJCs) after IP administration to streptozotocin (STZ)-induced diabetic mice. METHODS Type 1 diabetes (T1D) was induced in Kunming mice via IP injection of STZ. hUCWJCs were labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). Diabetic animals with sustained hyperglycemia for at least 2 weeks were administered 1 × 107 Dil-hUCWJCs via intraperitoneal injection. Insulin, glucagon and PDX-1 were detected by immunofluorescence with confocal microscopy. Serum mouse and human C-peptide was assayed in blood collected via intracardiac puncture. Specific β-cell differentiation markers and human DNA were assessed using qPCR performed with 200 ng of target DNA. RESULTS hUCWJCs migrated to the STZ-damaged organs and contributed to lower blood glucose levels in 30% of the treated mice. Confocal microscopy revealed the presence of resident insulin-positive cells in the liver and kidneys. hUCWJC-treated mice with restored hyperglycemia also showed increased serum mouse C-peptide levels. The qPCR results, particularly in the liver, revealed that after transplantation hUCWJCs upregulated genes of endocrine precursors but failed to express endocrine stage markers. Mice with restored hyperglycemia had reduced urinary volume and lacked glomerular hypertrophy, exhibiting a morphology resembling that of normal glomeruli. Moreover, we also verified that one of the possible mechanisms by which hUCWJCs exert immunosuppressive effects is through down-regulation of the cell surface receptor HLA-1. CONCLUSIONS We confirmed the potential of IP administration of hUCWJCs and the capability of these cells to migrate to damaged tissues and promote insulin secretion from non-pancreatic local cells and to improve renal damage. These findings confer unique therapeutic properties to hUCWJCs, suggesting a promising future in the treatment of diabetes mellitus.
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Affiliation(s)
- Martin Maldonado
- Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041 People’s Republic of China
- Translational Medical Center, Second Affiliated Hospital of Shantou University Medical College, 22 Xinling road, Shantou, Guangdong 515041 People’s Republic of China
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Research Center for Reproductive Medicine, Shantou University Medical College, Shantou, 515041 People’s Republic of China
- Reproductive Medicine & Genetics, Chengdu Jinjiang Hospital for Maternal & Child Health Care, Chengdu, 610066 China
| | - Tianhua Huang
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Research Center for Reproductive Medicine, Shantou University Medical College, Shantou, 515041 People’s Republic of China
- Reproductive Medicine & Genetics, Chengdu Jinjiang Hospital for Maternal & Child Health Care, Chengdu, 610066 China
| | - Lujun Yang
- Translational Medical Center, Second Affiliated Hospital of Shantou University Medical College, 22 Xinling road, Shantou, Guangdong 515041 People’s Republic of China
- Department of Burns and Plastic Surgery, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041 People’s Republic of China
| | - Lan Xu
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Research Center for Reproductive Medicine, Shantou University Medical College, Shantou, 515041 People’s Republic of China
| | - Lian Ma
- Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041 People’s Republic of China
- Translational Medical Center, Second Affiliated Hospital of Shantou University Medical College, 22 Xinling road, Shantou, Guangdong 515041 People’s Republic of China
- Department of Pediatrics, Maternal and Child Health Care Hospital of Shenzhen University, 518052 Shenzhen, Guangdong People’s Republic of China
- Department of Pediatrics, Maternal and Child Health Care Hospital of Pingshan District, 518122 Shenzhen, Guangdong People’s Republic of China
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30
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Zazzeroni L, Lanzoni G, Pasquinelli G, Ricordi C. Considerations on the harvesting site and donor derivation for mesenchymal stem cells-based strategies for diabetes. CELLR4-- REPAIR, REPLACEMENT, REGENERATION, & REPROGRAMMING 2017; 5:e2435. [PMID: 30505879 PMCID: PMC6267851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Mesenchymal Stem Cells (MSCs) possess important characteristics that could be exploited in therapeutic strategies for Type 1 Diabetes (T1D) and for certain complications of Type 2 Diabetes (T2D). MSCs can inhibit autoimmune, alloimmune and inflammatory processes. Moreover, they can promote the function of endogenous and transplanted pancreatic islets. Furthermore, they can stimulate angiogenesis. MSC functions are largely mediated by their secretome, which includes growth factors, exosomes, and other extracellular vesicles. MSCs have shown a good safety profile in clinical trials. MSC-derived exosomes are emerging as an alternative to the transplantation of live MSCs. MSCs harvested from different anatomical locations (e.g. bone marrow, umbilical cord, placenta, adipose tissue, and pancreas) have shown differences in gene expression profiles and function. Data from clinical trials suggest that umbilical cord-derived MSCs could be superior to bone marrow-derived MSCs for the treatment of T1D. Autologous MSCs from diabetic patients may present abnormal functions. BM-MSCs from T1D patients exhibit gene expression differences that may impact in vivo function. BM-MSCs from T2D patients seem to be significantly impaired due to the T2D diabetic milieu. In this review, we highlight how the harvesting site and donor derivation can affect the efficacy of MSC-based treatments for T1D and T2D.
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Affiliation(s)
- L Zazzeroni
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - G Lanzoni
- Diabetes Research Institute, University of Miami, Miami, FL, USA
| | - G Pasquinelli
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - C Ricordi
- Diabetes Research Institute, University of Miami, Miami, FL, USA
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31
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Carvalho FR, Fernandes AR, Cancela ML, Gavaia PJ. Improved regeneration and de novo bone formation in a diabetic zebrafish model treated with paricalcitol and cinacalcet. Wound Repair Regen 2017; 25:432-442. [PMID: 28380670 DOI: 10.1111/wrr.12536] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 03/15/2017] [Indexed: 02/06/2023]
Abstract
Bone changes related to diabetes have been well stablished, but few strategies have been developed to prevent this growing health problem. In our work, we propose to investigate the effects of calcitriol as well as of a vitamin D analog (paricalcitol) and a calcimimetic (cinacalcet), in fin regeneration and de novo mineralization in a zebrafish model of diabetes. Following exposure of diabetic transgenic Tg(ins:nfsb-mCherry) zebrafish to calcitriol, paricalcitol and cinacalcet, caudal fins were amputated to assess their effects on tissue regeneration. Caudal fin mineralized and regenerated areas were quantified by in vivo alizarin red staining. Quantitative real-time PCR was performed using RNA from the vertebral column. Diabetic fish treated with cinacalcet and paricalcitol presented increased regenerated and mineralized areas when compared with non-treated diabetic group, while no significant increase was observed in non-diabetic fish treated with both drugs. Gene expression analysis showed an up-regulation for runt-related transcription factor 2b (runx2b), bone gamma-carboxyglutamic acid-containing protein (bglap), insulin a (insa) and insulin b (insb) and a trend of increase for sp7 transcription factor (sp7) in diabetic groups treated with cinacalcet and paricalcitol. Expression of insra and vdra was up-regulated in both diabetic and nondiabetic fish treated with cinacalcet. In nondiabetic fish treated with paricalcitol and cinacalcet a similar increase in gene expression could be observed but not so pronounced. The increased mineralization and regeneration in diabetic zebrafish treated with cinacalcet and paricalcitol can be explained by increased osteoblastic differentiation and increased insulin expression indicating pro-osteogenic potential of both drugs.
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Affiliation(s)
- Filipe R Carvalho
- Center of Marine Sciences (CCMAR), Faro, Portugal.,PhD Program in Biomedical Sciences, University of Algarve, Faro, Portugal
| | - Ana R Fernandes
- Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal
| | - M Leonor Cancela
- Center of Marine Sciences (CCMAR), Faro, Portugal.,Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal
| | - Paulo J Gavaia
- Center of Marine Sciences (CCMAR), Faro, Portugal.,Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal
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32
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Mesenchymal stem cells and differentiated insulin producing cells are new horizons for pancreatic regeneration in type I diabetes mellitus. Int J Biochem Cell Biol 2017; 87:77-85. [PMID: 28385600 DOI: 10.1016/j.biocel.2017.03.018] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Revised: 03/24/2017] [Accepted: 03/28/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Diabetes mellitus has become the third human killer following cancer and cardiovascular disease. Millions of patients, often children, suffer from type 1 diabetes (T1D). Stem cells created hopes to regenerate damaged body tissues and restore their function. AIM This work aimed at clarifying and comparing the therapeutic potential of differentiated and non-differentiated mesenchymal stem cells (MSCs) as a new line of therapy for T1D. METHODS 40 Female albino rats divided into group I (control): 10 rats and group II (diabetic), III and IV, 10 rats in each, were injected with streptozotocin (50mg/kg body weight). Group III (MSCs) were transplanted with bone marrow derived MSCs from male rats and group IV (IPCs) with differentiated insulin producing cells. Blood and pancreatic tissue samples were taken from all rats for biochemical and histological studies. RESULTS MSCs reduced hyperglycemia in diabetic rats on day 15 while IPCs normalizes blood glucose level on day 7. Histological and morphometric analysis of pancreas of experimental diabetic rats showed improvement in MSCs-treated group but in IPCs-treated group, β-cells insulin immunoreactions were obviously returned to normal, with normal distribution of β-cells in the center and other cells at the periphery. Meanwhile, most of the pathological lesions were still detected in diabetic rats. CONCLUSION MSCs transplantation can reduce blood glucose level in recipient diabetic rats. IPCs initiate endogenous pancreatic regeneration by neogenesis of islets. IPCs are better than MSCs in regeneration of β-cells. So, IPCs therapy can be considered clinically to offer a hope for patients suffering from T1D.
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Itoh T, Nishinakamura H, Kumano K, Takahashi H, Kodama S. The Spleen Is an Ideal Site for Inducing Transplanted Islet Graft Expansion in Mice. PLoS One 2017; 12:e0170899. [PMID: 28135283 PMCID: PMC5279780 DOI: 10.1371/journal.pone.0170899] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 01/12/2017] [Indexed: 12/20/2022] Open
Abstract
Alternative islet transplantation sites have the potential to reduce the marginal number of islets required to ameliorate hyperglycemia in recipients with diabetes. Previously, we reported that T cell leukemia homeobox 1 (Tlx1)+ stem cells in the spleen effectively regenerated into insulin-producing cells in the pancreas of non-obese diabetic mice with end-stage disease. Thus, we investigated the spleen as a potential alternative islet transplantation site. Streptozotocin-induced diabetic C57BL/6 mice received syngeneic islets into the portal vein (PV), beneath the kidney capsule (KC), or into the spleen (SP). The marginal number of islets by PV, KC, or SP was 200, 100, and 50, respectively. Some plasma inflammatory cytokine levels in the SP group were significantly lower than those of the PV group after receiving a marginal number of islets, indicating reduced inflammation in the SP group. Insulin contents were increased 280 days after islet transplantation compared with those immediately following transplantation (p<0.05). Additionally, Tlx1-related genes, including Rrm2b and Pla2g2d, were up-regulated, which indicates that islet grafts expanded in the spleen. The spleen is an ideal candidate for an alternative islet transplantation site because of the resulting reduced inflammation and expansion of the islet graft.
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Affiliation(s)
- Takeshi Itoh
- Department of Regenerative Medicine & Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka, Japan
| | - Hitomi Nishinakamura
- Department of Regenerative Medicine & Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Kenjiro Kumano
- Department of Regenerative Medicine & Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka, Japan
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiroyuki Takahashi
- Department of Regenerative Medicine & Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka, Japan
- Department of Gastroenterological Surgery, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Shohta Kodama
- Department of Regenerative Medicine & Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka, Japan
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Ahangarpour A, Oroojan AA, Khorsandi L, Najimi SA. Pancreatic protective and hypoglycemic effects of Vitex agnus-castus L. fruit hydroalcoholic extract in D-galactose-induced aging mouse model. Res Pharm Sci 2017; 12:137-143. [PMID: 28515766 PMCID: PMC5385728 DOI: 10.4103/1735-5362.202452] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
D-galactose induces pancreatic disorder along with aging mouse model. Vitex agnus-castus (VAC) has potential pancreatic protective effect. Hence, this study was designed to evaluate the hypoglycemic and pancreas protective effects of VAC hydroalcoholic extract in D-galactose-induced aging female mice. In the present experimental study, 72 adult female Naval Medical Research Institute (NMRI) mice (weighing 30–35 g) were divided into 6 groups of control, VAC hydroalcoholic extract, D-galactose, D-galactose + VAC hydroalcoholic extract, aged, aged + VAC hydroalcoholic extract. The aged model was prepared by subcutaneous injection of D-galactose for 45 days and, VAC hydroalcoholic extract was gavaged twice a day in the last 7 days. 24 h after the last drug and extract administrations, serum samples and pancreatic tissues were removed to evaluate experimental and histological determinations. Serum glucose level decreased in VAC, D-galactose and, aged-treated groups compared to the control (P < 0.05). Insulin level increased in VAC and decreased in D-galactose and aged VAC-treated mice compared to the control (P < 0.05). Homeostasis model assessment-estimated insulin resistance (HOMA-IR) increased in D-galactose, aging, and VAC hydroalcoholic extract groups (P < 0.05) and, administration of VAC hydroalcoholic extract improved HOMA-IR in D-galactose and aging treated animals. Despite the size of pancreatic islets decreased in aged and D-galactose groups, VAC administration recovered it. Present data showed that VAC hydroalcoholic extract has hypoglycemic and pancreatic protective effects in natural aged and aging model mice.
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Affiliation(s)
- Akram Ahangarpour
- Health Research Institute, Diabetes Research Center, Department of Physiology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, I.R. Iran
| | - Ali Akbar Oroojan
- Department of Physiology, Student Research Committee of Ahvaz Jundishapur University of Medical Science, Ahvaz, I.R. Iran
| | - Layasadat Khorsandi
- Cell and Molecular Research Center, Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, I.R. Iran
| | - Seyedeh Asma Najimi
- Physiology Research Center, Department of Physiology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, I.R. Iran
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López IP, Piñeiro-Hermida S, Pais RS, Torrens R, Hoeflich A, Pichel JG. Involvement of Igf1r in Bronchiolar Epithelial Regeneration: Role during Repair Kinetics after Selective Club Cell Ablation. PLoS One 2016; 11:e0166388. [PMID: 27861515 PMCID: PMC5115747 DOI: 10.1371/journal.pone.0166388] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 10/27/2016] [Indexed: 12/14/2022] Open
Abstract
Regeneration of lung epithelium is vital for maintaining airway function and integrity. An imbalance between epithelial damage and repair is at the basis of numerous chronic lung diseases such as asthma, COPD, pulmonary fibrosis and lung cancer. IGF (Insulin-like Growth Factors) signaling has been associated with most of these respiratory pathologies, although their mechanisms of action in this tissue remain poorly understood. Expression profiles analyses of IGF system genes performed in mouse lung support their functional implication in pulmonary ontogeny. Immuno-localization revealed high expression levels of Igf1r (Insulin-like Growth Factor 1 Receptor) in lung epithelial cells, alveolar macrophages and smooth muscle. To further understand the role of Igf1r in pulmonary homeostasis, two distinct lung epithelial-specific Igf1r mutant mice were generated and studied. The lack of Igf1r disturbed airway epithelial differentiation in adult mice, and revealed enhanced proliferation and altered morphology in distal airway club cells. During recovery after naphthalene-induced club cell injury, the kinetics of terminal bronchiolar epithelium regeneration was hindered in Igf1r mutants, revealing increased proliferation and delayed differentiation of club and ciliated cells. Amid airway restoration, lungs of Igf1r deficient mice showed increased levels of Igf1, Insr, Igfbp3 and epithelial precursor markers, reduced amounts of Scgb1a1 protein, and alterations in IGF signaling mediators. These results support the role of Igf1r in controlling the kinetics of cell proliferation and differentiation during pulmonary airway epithelial regeneration after injury.
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Affiliation(s)
- Icíar P López
- Centro de Investigación Biomédica de la Rioja (CIBIR), Fundación Rioja Salud, Logroño, Spain
| | - Sergio Piñeiro-Hermida
- Centro de Investigación Biomédica de la Rioja (CIBIR), Fundación Rioja Salud, Logroño, Spain
| | - Rosete S Pais
- Centro de Investigación Biomédica de la Rioja (CIBIR), Fundación Rioja Salud, Logroño, Spain
| | - Raquel Torrens
- Centro de Investigación Biomédica de la Rioja (CIBIR), Fundación Rioja Salud, Logroño, Spain
| | - Andreas Hoeflich
- Institute of Genome Biology, Leibniz-Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - José G Pichel
- Centro de Investigación Biomédica de la Rioja (CIBIR), Fundación Rioja Salud, Logroño, Spain
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Wang W, Shi Q, Guo T, Yang Z, Jia Z, Chen P, Zhou C. PDX1 and ISL1 differentially coordinate with epigenetic modifications to regulate insulin gene expression in varied glucose concentrations. Mol Cell Endocrinol 2016; 428:38-48. [PMID: 26994512 DOI: 10.1016/j.mce.2016.03.019] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Revised: 02/26/2016] [Accepted: 03/15/2016] [Indexed: 01/01/2023]
Abstract
The mechanism of insulin gene transcription control in response to glucose concentration is poorly defined. The islet-restricted transcription factors PDX1 and ISL1 interact with BETA2, activating insulin gene expression. However, their contribution and hierarchical organization in insulin expression control based on glucose concentration remain unknown. We investigated PDX1 and ISL1 regulation of insulin gene expression in pancreatic β cells cultured in normal (5 mM/L) and high (25 mM/L) glucose conditions. ISL1 interacted with BETA2 to maintain basic insulin gene transcriptional activity under normal glucose. The ISL1-recruited cofactors SET9 and JMJD3 facilitated insulin gene histone modifications under normal glucose. In high-glucose concentrations, PDX1 formed a complex with BETA2 to enhance insulin gene expression. PDX1 also recruited SET9 and JMJD3 to promote the activation of histone modulation on the insulin promoter. This is the first evidence transcription factors orchestrate epigenetic modifications to control insulin gene expression based on glucose concentration.
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Affiliation(s)
- Weiping Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, 38 Xue Yuan Road, Beijing 100191, China
| | - Qiong Shi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, 38 Xue Yuan Road, Beijing 100191, China
| | - Ting Guo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, 38 Xue Yuan Road, Beijing 100191, China
| | - Zhe Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, 38 Xue Yuan Road, Beijing 100191, China
| | - Zhuqing Jia
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, 38 Xue Yuan Road, Beijing 100191, China
| | - Ping Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, 38 Xue Yuan Road, Beijing 100191, China
| | - Chunyan Zhou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, 38 Xue Yuan Road, Beijing 100191, China.
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Jiang FX, Morahan G. Insulin-secreting β cells require a post-genomic concept. World J Diabetes 2016; 7:198-208. [PMID: 27226815 PMCID: PMC4873311 DOI: 10.4239/wjd.v7.i10.198] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Accepted: 03/18/2016] [Indexed: 02/05/2023] Open
Abstract
Pancreatic insulin-secreting β cells are essential in maintaining normal glucose homeostasis accomplished by highly specialized transcription of insulin gene, of which occupies up to 40% their transcriptome. Deficiency of these cells causes diabetes mellitus, a global public health problem. Although tremendous endeavors have been made to generate insulin-secreting cells from human pluripotent stem cells (i.e., primitive cells capable of giving rise to all cell types in the body), a regenerative therapy to diabetes has not yet been established. Furthermore, the nomenclature of β cells has become inconsistent, confusing and controversial due to the lack of standardized positive controls of developmental stage-matched in vivo cells. In order to minimize this negative impact and facilitate critical research in this field, a post-genomic concept of pancreatic β cells might be helpful. In this review article, we will briefly describe how β cells were discovered and islet lineage is developed that may help understand the cause of nomenclatural controversy, suggest a post-genomic definition and finally provide a conclusive remark on future research of this pivotal cell.
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Saeinasab M, Matin MM, Rassouli FB, Bahrami AR. Blastema cells derived from New Zealand white rabbit's pinna carry stemness properties as shown by differentiation into insulin producing, neural, and osteogenic lineages representing three embryonic germ layers. Cytotechnology 2016; 68:497-507. [PMID: 25371011 PMCID: PMC4846631 DOI: 10.1007/s10616-014-9802-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Accepted: 10/24/2014] [Indexed: 10/24/2022] Open
Abstract
Stem cells (SCs) are known as undifferentiated cells with self-renewal and differentiation capacities. Regeneration is a phenomenon that occurs in a limited number of animals after injury, during which blastema tissue is formed. It has been hypothesized that upon injury, the dedifferentiation of surrounding tissues leads into the appearance of cells with SC characteristics. In present study, stem-like cells (SLCs) were obtained from regenerating tissue of New Zealand white rabbit's pinna and their stemness properties were examined by their capacity to differentiate toward insulin producing cells (IPCs), as well as neural and osteogenic lineages. Differentiation was induced by culture of SLCs in defined medium, and cell fates were monitored by specific staining, RT-PCR and flow cytometry assays. Our results revealed that dithizone positive cells, which represent IPCs, and islet-like structures appeared 1 week after induction of SLCs, and this observation was confirmed by the elevated expression of Ins, Pax6 and Glut4 at mRNA level. Furthermore, SLCs were able to express neural markers as early as 1 week after retinoic acid treatment. Finally, SLCs were able to differentiate into osteogenic lineage, as confirmed by Alizarin Red S staining and RT-PCR studies. In conclusion, SLCs, which could successfully differentiate into cells derived from all three germ layers, can be considered as a valuable model to study developmental biology and regenerative medicine.
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Affiliation(s)
- Morvarid Saeinasab
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Maryam M Matin
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.
- Cell and Molecular Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran.
| | - Fatemeh B Rassouli
- Cell and Molecular Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Ahmad Reza Bahrami
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
- Cell and Molecular Biotechnology Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
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Mustafa HN. The role of curcumin in streptozotocin-induced hepatic damage and the trans-differentiation of hepatic stellate cells. Tissue Cell 2016; 48:81-8. [DOI: 10.1016/j.tice.2016.02.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2015] [Revised: 01/19/2016] [Accepted: 02/07/2016] [Indexed: 10/22/2022]
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Carpino G, Puca R, Cardinale V, Renzi A, Scafetta G, Nevi L, Rossi M, Berloco PB, Ginanni Corradini S, Reid LM, Maroder M, Gaudio E, Alvaro D. Peribiliary Glands as a Niche of Extrapancreatic Precursors Yielding Insulin-Producing Cells in Experimental and Human Diabetes. Stem Cells 2016; 34:1332-42. [PMID: 26850087 DOI: 10.1002/stem.2311] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 12/02/2015] [Indexed: 12/22/2022]
Abstract
Peribiliary glands (PBGs) are niches in the biliary tree and containing heterogeneous endodermal stem/progenitors cells that can differentiate, in vitro and in vivo, toward pancreatic islets. The aim of this study was to evaluate, in experimental and human diabetes, proliferation of cells in PBGs and differentiation of the biliary tree stem/progenitor cells (BTSCs) toward insulin-producing cells. Diabetes was generated in mice by intraperitoneal injection of a single dose of 200 mg/kg (N = 12) or 120 mg/kg (N = 12) of streptozotocin. Liver, pancreas, and extrahepatic biliary trees were en bloc dissected and examined. Cells in PBGs proliferated in experimental diabetes, and their proliferation was greatest in the PBGs of the hepatopancreatic ampulla, and inversely correlated with the pancreatic islet area. In rodents, the cell proliferation in PBGs was characterized by the expansion of Sox9-positive stem/progenitor cells that gave rise to insulin-producing cells. Insulin-producing cells were located mostly in PBGs in the portion of the biliary tree closest to the duodenum, and their appearance was associated with upregulation of MafA and Gli1 gene expression. In patients with type 2 diabetes, PBGs at the level of the hepatopancreatic ampulla contained cells showing signs of proliferation and pancreatic fate commitment. In vitro, high glucose concentrations induced the differentiation of human BTSCs cultures toward pancreatic beta cell fates. The cells in PBGs respond to diabetes with proliferation and differentiation towards insulin-producing cells indicating that PBG niches may rescue pancreatic islet impairment in diabetes. These findings offer important implications for the pathophysiology and complications of this disease. Stem Cells 2016;34:1332-1342.
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Affiliation(s)
- Guido Carpino
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico,", Rome, Italy
| | - Rosa Puca
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Anastasia Renzi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Gaia Scafetta
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Lorenzo Nevi
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Massimo Rossi
- Department of General Surgery and Organ Transplantation, Sapienza University of Rome, Rome, Italy
| | - Pasquale B Berloco
- Department of General Surgery and Organ Transplantation, Sapienza University of Rome, Rome, Italy
| | - Stefano Ginanni Corradini
- Department of Clinical Medicine, Gastroenterology Division, Sapienza University of Rome, Rome, Italy
| | - Lola M Reid
- Department of Cell and Molecular Physiology, Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Marella Maroder
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Domenico Alvaro
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.,Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy
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Urabe H, Terashima T, Kojima H, Chan L. Ablation of a small subpopulation of diabetes-specific bone marrow-derived cells in mice protects against diabetic neuropathy. Am J Physiol Endocrinol Metab 2016; 310:E269-75. [PMID: 26695138 PMCID: PMC4971812 DOI: 10.1152/ajpendo.00381.2015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 12/14/2015] [Indexed: 12/28/2022]
Abstract
Diabetic peripheral neuropathy (DPN) is a major diabetic complication. Previously, we showed that hyperglycemia induces the appearance of proinsulin (PI)-producing bone marrow-derived cells (PI-BMDCs), which fuse with dorsal root ganglion neurons, causing apoptosis, nerve dysfunction, and DPN. In this study, we have devised a strategy to ablate PI-BMDCs in mice in vivo. The use of this strategy to selectively ablate TNFα-producing PI-BMDCs in diabetic mice protected these animals from developing DPN. The findings provide powerful validation for a pathogenic role of PI-BMDCs and identify PI-BMDCs as an accessible therapeutic target for the treatment and prevention of DPN.
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Affiliation(s)
- Hiroshi Urabe
- Division of Diabetes, Endocrinology, and Metabolism and the Diabetes Research Center, Departments of Medicine, Molecular and Cellular Biology, Biochemistry, and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; and
| | - Tomoya Terashima
- Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, Japan
| | - Hideto Kojima
- Division of Diabetes, Endocrinology, and Metabolism and the Diabetes Research Center, Departments of Medicine, Molecular and Cellular Biology, Biochemistry, and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; and Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, Japan
| | - Lawrence Chan
- Division of Diabetes, Endocrinology, and Metabolism and the Diabetes Research Center, Departments of Medicine, Molecular and Cellular Biology, Biochemistry, and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; and
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Knockin of Cre Gene at Ins2 Locus Reveals No Cre Activity in Mouse Hypothalamic Neurons. Sci Rep 2016; 6:20438. [PMID: 26830324 PMCID: PMC4735843 DOI: 10.1038/srep20438] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 01/04/2016] [Indexed: 12/20/2022] Open
Abstract
The recombination efficiency and cell specificity of Cre driver lines are critical for exploring pancreatic β cell biology with the Cre/LoxP approach. Some commonly used Cre lines are based on the short Ins2 promoter fragment and show recombination activity in hypothalamic neurons; however, whether this stems from endogenous Ins2 promoter activity remains controversial. In this study, we generated Ins2-Cre knockin mice with a targeted insertion of IRES-Cre at the Ins2 locus and demonstrated with a cell lineage tracing study that the Ins2 gene is not transcriptionally active in the hypothalamus. The Ins2-Cre driver line displayed robust Cre expression and activity in pancreatic β cells without significant alterations in insulin expression. In the brain, Cre activity was mainly restricted to the choroid plexus, without significant recombination detected in the hippocampus or hypothalamus by the LacZ or fluorescent tdTomato reporters. Furthermore, Ins2-Cre mice exhibited normal glucose tolerance and insulin secretion upon glucose stimulation in vivo. In conclusion, this Ins2-Cre driver line allowed high-fidelity detection of endogenous Ins2 promoter activity in vivo, and the negative activity in the hypothalamus demonstrated that this system is a promising alternative tool for studying β cell biology.
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Lin L, Lee JH, Buras ED, Yu K, Wang R, Smith CW, Wu H, Sheikh-Hamad D, Sun Y. Ghrelin receptor regulates adipose tissue inflammation in aging. Aging (Albany NY) 2016; 8:178-91. [PMID: 26837433 PMCID: PMC4761721 DOI: 10.18632/aging.100888] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Accepted: 01/20/2016] [Indexed: 12/30/2022]
Abstract
Aging is commonly associated with low-grade adipose inflammation, which is closely linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), increases in adipose tissues during aging, and old Ghsr(-/-) mice exhibit a lean and insulin-sensitive phenotype. Macrophages are major mediators of adipose tissue inflammation, which consist of pro-inflammatory M1 and anti-inflammatory M2 subtypes. Here, we show that in aged mice, GHS-R ablation promotes macrophage phenotypical shift toward anti-inflammatory M2. Old Ghsrp(-/-) mice have reduced macrophage infiltration, M1/M2 ratio, and pro-inflammatory cytokine expression in white and brown adipose tissues. We also found that peritoneal macrophages of old Ghsrp(-/-) mice produce higher norepinephrine, which is in line with increased alternatively-activated M2 macrophages. Our data further reveal that GHS-R has cell-autonomous effects in macrophages, and GHS-R antagonist suppresses lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Collectively, our studies demonstrate that ghrelin signaling has an important role in macrophage polarization and adipose tissue inflammation during aging. GHS-R antagonists may serve as a novel and effective therapeutic option for age-associated adipose tissue inflammation and insulin resistance.
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Affiliation(s)
- Ligen Lin
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
| | - Jong Han Lee
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Eric D. Buras
- Department of Internal Medicine at University of Michigan Health System, Ann Arbor, MI 48109, USA
| | - Kaijiang Yu
- Department of Intensive Care Unit, the Third Affiliated Hospital, Harbin Medical University, Harbin, 150081, China
| | - Ruitao Wang
- Department of Intensive Care Unit, the Third Affiliated Hospital, Harbin Medical University, Harbin, 150081, China
| | - C. Wayne Smith
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Huaizhu Wu
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - David Sheikh-Hamad
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yuxiang Sun
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
- Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA
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Gursoy UK, Liukkonen J, Jula A, Huumonen S, Suominen AL, Puukka P, Könönen E. Associations Between Salivary Bone Metabolism Markers and Periodontal Breakdown. J Periodontol 2015; 87:367-75. [PMID: 26609698 DOI: 10.1902/jop.2015.150399] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND A dual relationship between glycemic status and bone remodeling was suggested recently. The present study aimed to 1) analyze salivary levels of receptor activator for nuclear factor κ-B ligand (RANKL), osteoprotegerin, osteocalcin, and osteopontin as potential biomarkers of alveolar bone loss and 2) determine whether the glycemic status affects the relationship between bone remodeling markers and periodontal status. METHODS Salivary levels of RANKL, osteoprotegerin, osteocalcin, osteopontin, and serum glycosylated hemoglobin A1c, insulin, and glucose were analyzed in 220 participants divided into four groups according to their periodontal health status: 1) 79 participants had at least 14 teeth with probing depth (PD) ≥4 mm (generalized periodontitis [GP]); 2) 65 participants had either two or seven teeth with PD ≥4 mm (two groups of localized periodontitis [LP1 and LP2, respectively]); and 3) 76 participants had no teeth with PD ≥4 mm (non-periodontitis control group). RESULTS Salivary concentrations of RANKL, osteocalcin, and osteopontin were higher, and osteoprotegerin was lower in females than in males. Salivary osteoprotegerin concentrations were higher in the GP and LP2 groups than in the control group, whereas RANKL, osteocalcin, and osteopontin were not related with periodontal status. Salivary osteopontin correlated positively with serum and salivary insulin. The association observed between increased osteoprotegerin concentrations and periodontitis was lost after salivary insulin was included into the analyses as a confounding factor. CONCLUSIONS Salivary concentrations of bone markers are either affected by glycemic status or detected at very low levels. These factors hinder their use as salivary biomarkers of periodontitis.
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Affiliation(s)
- Ulvi K Gursoy
- Institute of Dentistry, University of Turku, Turku, Finland
| | | | - Antti Jula
- Department of Diagnostic Imaging, Turku University Hospital, Turku, Finland
| | - Sisko Huumonen
- Institute of Dentistry, University of Turku, Turku, Finland.,National Institute for Health and Welfare, Turku, Finland
| | - Anna L Suominen
- Unit of Living Conditions, Health, and Wellbeing and Department of Environmental Health in Environmental Epidemiology Unit; National Institute for Health and Welfare; Kuopio, Finland.,Institute of Dentistry, University of Eastern Finland, Kuopio, Finland.,Department of Oral and Maxillofacial Surgery, Kuopio University Hospital, Kuopio, Finland
| | - Pauli Puukka
- Department of Diagnostic Imaging, Turku University Hospital, Turku, Finland
| | - Eija Könönen
- Institute of Dentistry, University of Turku, Turku, Finland.,Oral Health Care, Welfare Division, City of Turku, Turku, Finland
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Opposite Expression of SPARC between the Liver and Pancreas in Streptozotocin-Induced Diabetic Rats. PLoS One 2015; 10:e0131189. [PMID: 26110898 PMCID: PMC4481468 DOI: 10.1371/journal.pone.0131189] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 05/30/2015] [Indexed: 12/30/2022] Open
Abstract
Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that regulates several cellular events, including inflammation and tissue remodelling. In this study, we investigated the tissue-specific expression of SPARC in streptozotocin (STZ)-induced diabetes, and found that SPARC was significantly up-regulated in the liver while down-regulated in the pancreas of STZ-induced diabetic rats. Chronic inflammation occurred in the diabetic pancreas accompanied by up-regulation of CCAAT/enhancer-binding protein beta (C/EBPβ) and its targets (TNFα, Il6, CRP, and Fn1) as well as myeloperoxidase (Mpo) and C-X-C chemokine receptor type 2 (Cxcr2). Diabetic liver showed significant up-regulation of Tgfb1 as well as moderately less up-regulated TNFα and reduced Fn1, resulting in elevated fibrogenesis. PARP-1 was not up-regulated during CD95-mediated apoptosis, resulting in restoration of high ATP levels in the diabetic liver. On the contrary, CD95-dependent apoptosis was not observed in the diabetic pancreas due to up-regulation of PARP-1 and ATP depletion, resulting in necrosis. The cytoprotective machinery was damaged by pancreatic inflammation, whereas adequate antioxidant capacity indicates low oxidative stress in the diabetic liver. High and low cellular insulin content was found in the diabetic liver and pancreas, respectively. Furthermore, we identified six novel interacting partner proteins of SPARC by co-immunoprecipitation in the diabetic liver and pancreas, and their interactions with SPARC were predicted by bioinformatics tools. Taken together, opposite expression of SPARC in the diabetic liver and pancreas may be related to inflammation and immune cell infiltration, degrees of apoptosis and fibrosis, cytoprotective machinery, and cellular insulin levels.
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46
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Buras ED, Yang L, Saha P, Kim J, Mehta P, Yang Y, Hilsenbeck S, Kojima H, Chen W, Smith CW, Chan L. Proinsulin-producing, hyperglycemia-induced adipose tissue macrophages underlie insulin resistance in high fat-fed diabetic mice. FASEB J 2015; 29:3537-48. [PMID: 25953849 DOI: 10.1096/fj.15-271452] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Accepted: 04/27/2015] [Indexed: 12/20/2022]
Abstract
Adipose tissue macrophages (ATMs) play an important role in the pathogenesis of obese type 2 diabetes. High-fat diet (HFD)-induced obesity has been shown to lead to ATM accumulation in rodents; however, the impact of hyperglycemia on ATM dynamics in HFD-fed type 2 diabetic models has not been studied. We previously showed that hyperglycemia induces the appearance of proinsulin (PI)-producing proinflammatory bone marrow (BM)-derived cells (PI-BMDCs) in rodents. We fed a 60% HFD to C57BL6/J mice to produce an obese type 2 diabetes model. Absent in chow-fed animals, PI-BMDCs account for 60% of the ATMs in the type 2 diabetic mice. The PI-ATM subset expresses TNF-α and other inflammatory markers, and is highly enriched within crownlike structures (CLSs). We found that amelioration of hyperglycemia by different hypoglycemic agents forestalled PI-producing ATM accumulation and adipose inflammation in these animals. We developed a diphtheria toxin receptor-based strategy to selectively ablate PI-BMDCs among ATMs. Application of the maneuver in HFD-fed type 2 diabetic mice was found to lead to near total disappearance of complex CLSs and reversal of insulin resistance and hepatosteatosis in these animals. In sum, we have identified a novel ATM subset in type 2 diabetic rodents that underlies systemic insulin resistance.
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Affiliation(s)
- Eric Dale Buras
- *Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA; Children's Nutrition Research Center, U.S. Department of Agriculture, Houston, Texas, USA; and Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Lina Yang
- *Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA; Children's Nutrition Research Center, U.S. Department of Agriculture, Houston, Texas, USA; and Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Pradip Saha
- *Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA; Children's Nutrition Research Center, U.S. Department of Agriculture, Houston, Texas, USA; and Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Jongoh Kim
- *Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA; Children's Nutrition Research Center, U.S. Department of Agriculture, Houston, Texas, USA; and Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Pooja Mehta
- *Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA; Children's Nutrition Research Center, U.S. Department of Agriculture, Houston, Texas, USA; and Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Yisheng Yang
- *Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA; Children's Nutrition Research Center, U.S. Department of Agriculture, Houston, Texas, USA; and Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Susan Hilsenbeck
- *Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA; Children's Nutrition Research Center, U.S. Department of Agriculture, Houston, Texas, USA; and Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Hideto Kojima
- *Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA; Children's Nutrition Research Center, U.S. Department of Agriculture, Houston, Texas, USA; and Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Wenhao Chen
- *Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA; Children's Nutrition Research Center, U.S. Department of Agriculture, Houston, Texas, USA; and Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - C Wayne Smith
- *Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA; Children's Nutrition Research Center, U.S. Department of Agriculture, Houston, Texas, USA; and Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Lawrence Chan
- *Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA; Children's Nutrition Research Center, U.S. Department of Agriculture, Houston, Texas, USA; and Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
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Okano J, Kojima H, Katagi M, Nakae Y, Terashima T, Nakagawa T, Kurakane T, Okamoto N, Morohashi K, Maegawa H, Udagawa J. Epidermis-dermis junction as a novel location for bone marrow-derived cells to reside in response to ionizing radiation. Biochem Biophys Res Commun 2015; 461:695-701. [PMID: 25922286 DOI: 10.1016/j.bbrc.2015.04.094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 04/19/2015] [Indexed: 11/17/2022]
Abstract
Bone marrow-derived cells (BMDCs) can migrate into the various organs in the mice irradiated by ionizing radiation (IR). However, it may not be the case in the skin. While IR is used for bone marrow (BM) transplantation, studying with the epidermal sheets demonstrated that the BMDC recruitment is extraordinarily rare in epidermis in the mouse. Herein, using the chimera mice with BM from green fluorescent protein (GFP) transgenic mice, we simply examined if BMDCs migrate into any layers in the total skin, as opposed to the epidermal sheets, in response to IR. Interestingly, we identified the presence of GFP-positive (GFP(+)) cells in the epidermis-dermis junction in the total skin sections although the epidermal cell sheets failed to have any GFP cells. To examine a possibility that the cells in the junction could be mechanically dissociated during separating epidermal sheets, we then salvaged such dissociated cells and examined its characteristics. Surprisingly, some GFP(+) cells were found in the salvaged cells, indicating that these cells could be derived from BM. In addition, such BMDCs were also associated with inflammation in the junction. In conclusion, BMDCs can migrate to and reside in the epidermis-dermis junction after IR.
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Affiliation(s)
- Junko Okano
- Division of Anatomy and Cell Biology, Shiga University of Medical Science, Shiga, Japan.
| | - Hideto Kojima
- Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Shiga, Japan
| | - Miwako Katagi
- Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Shiga, Japan
| | - Yuki Nakae
- Department of Internal Medicine, Shiga University of Medical Science, Shiga, Japan
| | - Tomoya Terashima
- Department of Stem Cell Biology and Regenerative Medicine, Shiga University of Medical Science, Shiga, Japan
| | - Takahiko Nakagawa
- TMK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takeshi Kurakane
- Division of Anatomy and Cell Biology, Shiga University of Medical Science, Shiga, Japan
| | - Naoki Okamoto
- Division of Anatomy and Cell Biology, Shiga University of Medical Science, Shiga, Japan
| | - Keita Morohashi
- Division of Anatomy and Cell Biology, Shiga University of Medical Science, Shiga, Japan
| | - Hiroshi Maegawa
- Department of Internal Medicine, Shiga University of Medical Science, Shiga, Japan
| | - Jun Udagawa
- Division of Anatomy and Cell Biology, Shiga University of Medical Science, Shiga, Japan
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Calafiore R, Basta G. Stem cells for the cell and molecular therapy of type 1 diabetes mellitus (T1D): the gap between dream and reality. AMERICAN JOURNAL OF STEM CELLS 2015; 4:22-31. [PMID: 25973328 PMCID: PMC4396156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 11/14/2014] [Indexed: 06/04/2023]
Abstract
In spite of intense research, over the past 2-3 decades, targeted to validating methods for the cure of T1D, based on cell substitution therapy in the place of exogenously administered insulin injections, achievement of the final goal continues to remain out of reach. In fact, aside of very limited clinical success of the few clinical trials of pancreatic islet cell transplantation in totally immunosuppressed patients with T1D, the vast majority of these diabetic patients invariably is insulin-dependent. New advances for cell and molecular therapy for T1D, including use of stem cells, are reviewed and discussed in an attempt to clearly establish where we are and where are we may go for the final cure for T1DM.
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Affiliation(s)
- Riccardo Calafiore
- Department of Medicine, Section of Clinical Cardiovascular, Endocrine and Metabolic Physiology, University of Perugia School of Medicine at Terni Terni, Italy
| | - Giuseppe Basta
- Department of Medicine, Section of Clinical Cardiovascular, Endocrine and Metabolic Physiology, University of Perugia School of Medicine at Terni Terni, Italy
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Lipid droplets hypertrophy: a crucial determining factor in insulin regulation by adipocytes. Sci Rep 2015; 5:8816. [PMID: 25743104 PMCID: PMC4649717 DOI: 10.1038/srep08816] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 01/27/2015] [Indexed: 01/14/2023] Open
Abstract
Lipid droplets (LDs) hypertrophy in adipocytes is the main cause of energy metabolic system dysfunction, obesity and its afflictions such as T2D. However, the role of adipocytes in linking energy metabolic disorders with insulin regulation is unknown in humans. Human adipocytes constitutively synthesize and secrete insulin, which is biologically functional. Insulin concentrations and release are fat mass- and LDs-dependent respectively. Fat reduction mediated by bariatric surgery repairs obesity-associated T2D. The expression of genes, like PCSK1 (proinsulin conversion enzyme), GCG (Glucagon), GPLD1, CD38 and NNAT, involved in insulin regulation/release were differentially expressed in pancreas and adipose tissue (AT). INS (insulin) and GCG expression reduced in human AT-T2D as compared to AT-control, but remained unchanged in pancreas in either state. Insulin levels (mRNA/protein) were higher in AT derived from prediabetes BB rats with destructed pancreatic β-cells and controls than pancreas derived from the same rats respectively. Insulin expression in 10 human primary cell types including adipocytes and macrophages is an evidence for extrapancreatic insulin-producing cells. The data suggest a crosstalk between AT and pancreas to fine-tune energy metabolic system or may minimize the metabolic damage during diabetes. This study opens new avenues towards T2D therapy with a great impact on public health.
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50
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Urabe H, Terashima T, Lin F, Kojima H, Chan L. Bone marrow-derived TNF-α causes diabetic neuropathy in mice. Diabetologia 2015; 58:402-10. [PMID: 25399355 PMCID: PMC4289451 DOI: 10.1007/s00125-014-3440-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 10/14/2014] [Indexed: 12/26/2022]
Abstract
AIMS/HYPOTHESIS Dysregulation of biochemical pathways in response to hyperglycaemia in cells intrinsic to the nervous system (Schwann cells, neurons, vasa nervorum) are thought to underlie diabetic peripheral neuropathy (DPN). TNF-α is a known aetiological factor; Tnf-knockout mice are protected against DPN. We hypothesised that TNF-α produced by a small but specific bone marrow (BM) subpopulation marked by proinsulin production (proinsulin-producing BM-derived cells, PI-BMDCs) is essential for DPN development. METHODS We produced mice deficient in TNF-α, globally in BM and selectively in PI-BMDCs only, by gene targeting and BM transplantation, and induced diabetes by streptozotocin. Motor and sensory nerve conduction velocities were used to gauge nerve dysfunction. Immunocytochemistry, fluorescence in situ hybridisation (FISH) and PCR analysis of dorsal root ganglia (DRG) were employed to monitor outcome. RESULTS We found that loss of TNF-α in BM only protected mice from DPN. We developed a strategy to delete TNF-α specifically in PI-BMDCs, and found that PI-BMDC-specific loss of TNF-α protected against DPN as robustly as loss of total BM TNF-α. Selective loss of PI-BMDC-derived TNF-α downregulated TUNEL-positive DRG neurons. FISH revealed PI-BMDC-neuron fusion cells in the DRG in mice with DPN; fusion cells were undetectable in non-diabetic mice or diabetic mice that had lost TNF-α expression selectively in the PI-BMDC subpopulation. CONCLUSIONS/INTERPRETATION BMDC-specific TNF-α is essential for DPN development; its selective removal from a small PI-BMDC subpopulation protects against DPN. The pathogenicity of PI-BMDC-derived TNF-α may have important therapeutic implications.
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Affiliation(s)
- Hiroshi Urabe
- Department of Medicine, Baylor College of Medicine, One Baylor Plaza (MS: BCM185), Houston, TX, 77030, USA
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