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Exp Clin Endocrinol Diabetes 2013; 121(10): 607-613
DOI: 10.1055/s-0033-1354380
Article
© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

p21 is Associated with the Proliferation and Apoptosis of Bone Marrow-derived Mesenchymal Stem Cells from Non-obese Diabetic Mice

Z. Gu
1   Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, P. R. China
,
J. Jiang
1   Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, P. R. China
,
Y. Xia
1   Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, P. R. China
,
X. Yue
2   State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
,
M. Yan
1   Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, P. R. China
,
T. Tao
3   Department of Immunology, Medical College, Nantong University, ­Nantong, P. R. China
,
X. Cao
4   Department of Pathology, Nantong University, Nantong, P. R. China
,
Z. Da
1   Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, P. R. China
,
H. Liu
5   Department of Hematology, Affiliated Hospital of Nantong University, Nantong, P. R. China
,
H. Liu
1   Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, P. R. China
,
Y. Miao
6   Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P. R. China
,
L. Li
7   Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, P. R. China
,
Z. Wang
8   Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, P. R. China
› Author Affiliations
Further Information

Publication History

received 10 May 2013
first decision 08 August 2013

accepted 14 August 2013

Publication Date:
25 November 2013 (online)

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Abstract

Recent studies have shown that autologous and allogeneic transplantation of the BM-MSCs had therapeutic effects on T1DM, whereas the BM-MSCs from the NOD mice itself did not have this therapeutic effect. We previously demonstrated that Bone Marrow (BM) -MSCs from the non-obese diabetic (NOD) mice had the abnormal migration and adhesion. So we hypothesized that the proliferation and apoptosis of the BM-MSCs from the NOD mice were dysregulated. Our team compared the proliferation and apoptosis between NOD mice and imprinting control region (ICR) mice. Then we assessed whether the NF-κB-p53/p21 pathway was involved in the process. The cell proliferation ability of the BM-MSCs from the NOD mice were significantly decreased, while the percent of apoptotic cells was increased compared to those from the ICR mice. The p21 expression was significantly increased in the NOD-MSCs. The p65 level was enhanced in the BM-MSCs from the NOD mice when compared to the ICR mice, coincided with the expression of p21. Expressions of p65 and p21 were significantly decreased in the ­BM-MSCs treated with p65 inhibitor. The knockdown p21 expression reversed the abnormal proliferation, colony formation and apoptosis of the BM-MSCs from the NOD mice. These data provide important preclinical references supporting the basis for further development of autologous MSC-based therapies for type1 diabetes mellitus (T1DM).

Key words

diabetes - Graves’ disease - thyroid
 

  • References

  • 1 Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 2010; 464: 1293-1300
    CrossrefPubMedGoogle Scholar
  • 2 Roep BO. The role of T-cells in the pathogenesis of Type 1 diabetes: from cause to cure. Diabetologia 2003; 46: 305-321
    PubMedGoogle Scholar
  • 3 Bottazzo GF, Dean BM, McNally JM et al. In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. N Engl J Med 1985; 313: 353-360
    CrossrefPubMedGoogle Scholar
  • 4 Pittenger MF, Mackay AM, Beck SC et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143-147
    CrossrefPubMedGoogle Scholar
  • 5 Kassem M. Mesenchymal stem cells: biological characteristics and potential clinical applications. Cloning Stem Cells 2004; 6: 369-374
    CrossrefPubMedGoogle Scholar
  • 6 Aldahmash A, Zaher W, Al-Nbaheen M et al. Human stromal (mesenchymal) stem cells: basic biology and current clinical use for tissue regeneration. Ann Saudi Med 2012; 32: 68-77
    PubMedGoogle Scholar
  • 7 Le Blanc K, Tammik L, Sundberg B et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 2003; 57: 11-20
    CrossrefPubMedGoogle Scholar
  • 8 Krampera M, Glennie S, Dyson J et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003; 101: 3722-3729
    CrossrefPubMedGoogle Scholar
  • 9 Tse WT, Pendleton JD, Beyer WM et al. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 2003; 75: 389-397
    CrossrefPubMedGoogle Scholar
  • 10 Kadam SS, Bhonde RR. Islet neogenesis from the constitutively nestin expressing human umbilical cord matrix derived mesenchymal stem cells. Islets 2010; 2: 112-120
    CrossrefPubMedGoogle Scholar
  • 11 Chen LB, Jiang XB, Yang L. Differentiation of rat marrow mesenchymal stem cells into pancreatic islet beta-cells. World J Gastroenterol 2004; 10: 3016-3020
    PubMedGoogle Scholar
  • 12 Gao F, Wu DQ, Hu YH et al. In vitro cultivation of islet-like cell clusters from human umbilical cord blood-derived mesenchymal stem cells. Transl Res 2008; 151: 293-302
    CrossrefPubMedGoogle Scholar
  • 13 Wang HS, Shyu JF, Shen WS et al. Transplantation of insulin-producing cells derived from umbilical cord stromal mesenchymal stem cells to treat NOD mice. Cell Transplantation 2011; 20: 455-466
    CrossrefPubMedGoogle Scholar
  • 14 Fiorina P, Jurewicz M, Augello A et al. Immunomodulatory function of bone marrow-derived mesenchymal stem cells in experimental autoimmune type 1 diabetes. J Immunol 2009; 183: 993-1004
    CrossrefPubMedGoogle Scholar
  • 15 Li L, Xia Y, Wang Z et al. Suppression of the PI3K-Akt pathway is involved in the decreased adhesion and migration of bone marrow-derived mesenchymal stem cells from non-obese diabetic mice. Cell Biol Int 2011; 35: 961-966
    CrossrefPubMedGoogle Scholar
  • 16 Xu Y, Gu Z, Shen B et al. Roles of Wnt/β-Catenin Signaling in retinal neuron-like differentiation of bone marrow mesenchymal stem cells from non-obese diabetic mice. J Mol Neurosci 2013; 49: 250-261
    CrossrefPubMedGoogle Scholar
  • 17 Li X, Liu L, Meng D et al. Enhanced Apoptosis and Senescence of Bone-Marrow-Derived Mesenchymal Stem Cells in Patients with Systemic Lupus Erythematosus. Stem Cells Dev 2012; 21: 2387-2394
    CrossrefPubMedGoogle Scholar
  • 18 Gu Z, Cao X, Jiang J et al. Upregulation of p16(INK4A) promotes cellular senescence of bone marrow-derived mesenchymal stem cells from systemic lupus erythematosus patients. Cell Signal 2012; 24: 2307-2314
    CrossrefPubMedGoogle Scholar
  • 19 Waga S, Hannon GJ, Beach D et al. The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature 1994; 369: 574-578
    CrossrefPubMedGoogle Scholar
  • 20 Harper JW, Adami GR, Wei N et al. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 1993; 75: 805-816
    CrossrefPubMedGoogle Scholar
  • 21 Cmielová J, Rezáčová M. p21Cip1/Waf1 protein and its function based on a subcellular localization [corrected]. J Cell Biochem 2011; 112: 3502-3506
    CrossrefPubMedGoogle Scholar
  • 22 Cmielová J, Havelek R, Jiroutová A et al. DNA damage caused by ionizing radiation in embryonic diploid fibroblasts WI-38 induces both apoptosis and senescence. Physiol Res 2011; 60: 667-677
    PubMedGoogle Scholar
  • 23 Yew TL, Chiu FY, Tsai CC et al. Knockdown of p21(Cip1/Waf1) enhances proliferation, the expression of stemness markers, and osteogenic potential in human mesenchymal stem cells. Aging Cell 2011; 10: 349-361
    CrossrefPubMedGoogle Scholar
  • 24 Choudhery MS, Khan M, Mahmood R et al. Bone marrow derived mesenchymal stem cells from aged mice have reduced wound healing, angiogenesis, proliferation and anti-apoptosis capabilities. Cell Biol Int 2012; 36: 747-753
    CrossrefPubMedGoogle Scholar
  • 25 Roque T, Haton C, Etienne O et al. Lack of a p21waf1/cip -dependent G1/S checkpoint in neural stem and progenitor cells after DNA damage in vivo. Stem Cells 2012; 30: 537-547
    CrossrefPubMedGoogle Scholar
  • 26 Yan X, Lv A, Xing Y et al. Inhibition of p53-p21 pathway promotes the differentiation of rat bone marrow mesenchymal stem cells into cardiomyocytes. Mol Cell Biochem 2011; 354: 21-28
    CrossrefPubMedGoogle Scholar
  • 27 Liang W, Lu C, Li J et al. p73alpha regulates the sensitivity of bone marrow mesenchymal stem cells to DNA damage agents. Toxicology 2010; 270: 49-56
    CrossrefPubMedGoogle Scholar
  • 28 Mankan AK, Lawless MW, Gray SG et al. NF-kappaB regulation: the nuclear response. J Cell Mol Med 2009; 13: 631-643
    CrossrefPubMedGoogle Scholar
  • 29 Dejardin E. The alternative NF-kappaB pathway from biochemistry to biology: pitfalls and promises for future drug development. Biochem Pharmacol 2006; 72: 1161-1179
    CrossrefPubMedGoogle Scholar
  • 30 Shimizu H, Bolati D, Adijiang A et al. NF-κB plays an important role in indoxyl sulfate-induced cellular senescence, fibrotic gene expression, and inhibition of proliferation in proximal tubular cells. Am J Physiol Cell Physiol 2011; 301: 1201-1212
    CrossrefPubMedGoogle Scholar
  • 31 Lin YJ, Huang YH, Zhen YZ et al. Rhein lysinate induces apoptosis in breast cancer SK-Br-3 cells by inhibiting HER-2 signal pathway. Yao Xue Xue Bao 2008; 43: 1099-1105
    PubMedGoogle Scholar
  • 32 Yao J, Qian CJ, Ye B et al. ERK inhibition enhances TSA-induced gastric cancer cell apoptosis via NF-κB-dependent and Notch-independent mechanism. Life Sci 2012; 91: 186-193
    CrossrefPubMedGoogle Scholar
  • 33 Rodríguez-Vilarrupla A, Jaumot M, Abella N et al. Binding of calmodulin to the carboxy-terminal region of p21 induces nuclear accumulation via inhibition of protein kinase C-mediated phosphorylation of Ser153. Mol Cell Biol 2005; 25: 7364-7374
    CrossrefPubMedGoogle Scholar
  • 34 Fukuchi K, Watanabe H, Tomoyasu S et al. Phosphatidylinositol 3-kinase inhibitors, Wortmannin or LY294002, inhibited accumulation of p21 protein after gamma-irradiation by stabilization of the protein. Biochim Biophys Acta 2000; 1496: 207-220
    CrossrefPubMedGoogle Scholar
  • 35 Feng X, Lu B, Xu Y et al. Aspirin reduces the apoptotic effect of etoposide via Akt activation and up-regulation of p21(cip). Int J Mol Med 2011; 28: 637-643
    PubMedGoogle Scholar
  • 36 van den Heuvel S. Cell-cycle regulation. WormBook 2005; 1-16
    CrossrefPubMedGoogle Scholar
  • 37 Zhang DY, Wang HJ, Tan YZ. Wnt/beta-catenin signaling induces the aging of mesenchymal stem cells through the DNA damage response and the p53/p21 pathway. PLoS One 2011; 6: 21397
    CrossrefPubMedGoogle Scholar
  • 38 Cmielova J, Havelek R, Soukup T et al. Gamma radiation induces senescence in human adult mesenchymal stem cells from bone marrow and periodontal ligaments. Int J Radiat Biol 2012; 88: 393-404
    CrossrefPubMedGoogle Scholar
  • 39 Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999; 13: 1501-1512
    CrossrefPubMedGoogle Scholar
  • 40 Zeeb M, Rösner H, Zeslawski W et al. Protein folding and stability of human CDK inhibitor p19(INK4d). J Mol Biol 2002; 315: 447-457
    CrossrefPubMedGoogle Scholar