RESEARCH ARTICLE

Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome

  • Zeming Wu 1,2,3 ,
  • Weiqi Zhang 2,3,4 ,
  • Moshi Song 3,5 ,
  • Wei Wang 2,3 ,
  • Gang Wei 6 ,
  • Wei Li 4 ,
  • Jinghui Lei 4 ,
  • Yu Huang 7 ,
  • Yanmei Sang 8 ,
  • Piu Chan 4 ,
  • Chang Chen 2,3 ,
  • Jing Jing , 1,3 ,
  • Keiichiro Suzuki , 9,10 ,
  • Juan Carlos Izpisua Belmonte , 11 ,
  • Guang-Hui Liu , 2,3,4,12
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  • 1. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
  • 2. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
  • 3. University of Chinese Academy of Sciences, Beijing 100049, China
  • 4. National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
  • 5. State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
  • 6. Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
  • 7. Department of Medical genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
  • 8. Department of Pediatric Endocrinology and Genetic Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China
  • 9. Institute for Advanced Co-Creation Studies, Osaka University, Osaka 560-8531, Japan
  • 10. Graduate School of Engineering Science, Osaka University, Osaka 560-8531, Japan
  • 11. Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla 92037, USA
  • 12. Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China

Received date: 18 Jan 2018

Accepted date: 08 Feb 2018

Published date: 27 Apr 2018

Copyright

2018 The Author(s) 2018. This article is an open access publication

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product—progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNAmutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.

Cite this article

Zeming Wu , Weiqi Zhang , Moshi Song , Wei Wang , Gang Wei , Wei Li , Jinghui Lei , Yu Huang , Yanmei Sang , Piu Chan , Chang Chen , Jing Jing , Keiichiro Suzuki , Juan Carlos Izpisua Belmonte , Guang-Hui Liu . Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome[J]. Protein & Cell, 2018 , 9(4) : 333 -350 . DOI: 10.1007/s13238-018-0517-8

1
Adelfalk C, Scherthan H, Hirsch-Kauffmann M, Schweiger M (2005) Nuclear deformation characterizes Werner syndrome cells. Cell Bbiol Int 29:1032–1037

DOI

2
Atchison L, Zhang H, Cao K, Truskey GA (2017) A tissue engineered blood vessel model of Hutchinson-Gilford progeria syndrome using human iPSC-derived smooth muscle cells. Sci Rep 7:8168

DOI

3
Bochenek ML, Schutz E, Schafer K (2016) Endothelial cell senescence and thrombosis: ageing clots. Thromb Res 147:36–45

DOI

4
Brunauer R, Kennedy BK (2015) Medicine. Progeria accelerates adult stem cell aging. Science 348:1093–1094

DOI

5
Buchwalter A, Hetzer MW (2017) Nucleolar expansion and elevated protein translation in premature aging. Nat Commun 8:328

DOI

6
Burtner CR, Kennedy BK (2010) Progeria syndromes and ageing: what is the connection? Nat Rev Mol Cell Biol 11:567–578

DOI

7
Cao K, Blair CD, Faddah DA, Kieckhaefer JE, Olive M, Erdos MR, Nabel EG, Collins FS (2011) Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts. J Clin Investig 121:2833–2844

DOI

8
Chen Z, Chang WY, Etheridge A, Strickfaden H, Jin Z, Palidwor G, Cho JH, Wang K, Kwon SY, Dore C (2017) Reprogramming progeria fibroblasts re-establishes a normal epigenetic landscape. Aging Cell 16:870–887

DOI

9
Cheung HH, Liu X, Canterel-Thouennon L, Li L, Edmonson C, Rennert OM (2014) Telomerase protects werner syndrome lineage-specific stem cells from premature aging. Stem Cell Rep 2:534–546

DOI

10
Cheung HH, Pei D, Chan WY (2015) Stem cell aging in adult progeria. Cell Regener 4:6

DOI

11
Choi S, Wang W, Ribeiro AJ, Kalinowski A, Gregg SQ, Opresko PL, Niedernhofer LJ, Rohde GK, Dahl KN (2011) Computational image analysis of nuclear morphology associated with various nuclear-specific aging disorders. Nucleus 2:570–579

DOI

12
Chojnowski A, Ong PF, Dreesen O (2015) Nuclear lamina remodelling and its implications for human disease. Cell Tissue Res 360:621–631

DOI

13
Compagnucci C, Bertini E (2017) The Potential of iPSCs for the treatment of premature aging disorders. Int J Mol Sci 18:2350

DOI

14
Cox LS, Faragher RG (2007) From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing. Cell Mol Life Sci: CMLS 64:2620–2641

DOI

15
De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, Lyonnet S, Stewart CL, Munnich A, Le Merrer M (2003) Lamin a truncation in Hutchinson-Gilford progeria. Science 300:2055

DOI

16
DeBoy E, Puttaraju M, Jailwala P (2017) Identification of novel RNA isoforms of LMNA. Nucleus 8:573–582

DOI

17
Ding SL, Shen CY (2008) Model of human aging: recent findings on Werner’s and Hutchinson-Gilford progeria syndromes. Clin Interv Aging 3:431–444

DOI

18
Dreesen O, Stewart CL (2011) Accelerated aging syndromes, are they relevant to normal human aging? Aging 3:889–895

DOI

19
Duan S, Yuan G, Liu X, Ren R, Li J, Zhang W, Wu J (2015) PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype. Nat Commun 6:10068

DOI

20
Egesipe AL, Blondel S, Cicero AL, Jaskowiak AL, Navarro C, Sandre-Giovannoli A, Levy N, Peschanski M, Nissan X (2016) Metformin decreases progerin expression and alleviates pathological defects of Hutchinson-Gilford progeria syndrome cells. npj Aging Mech Dis 2:16026

DOI

21
Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P (2003) Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423:293–298

DOI

22
Fang B, Li Y, Song Y, Li N (2010) Isolation and characterization of multipotent progenitor cells from the human fetal aorta wall. Exp Biol Med 235:130–138

DOI

23
Fu L, Xu X, Ren R, Wu J, Zhang W, Yang J, Ren X, Wang S, Zhao Y, Sun L (2016) Modeling xeroderma pigmentosum associated neurological pathologies with patients-derived iPSCs. Protein Cell 7:210–221

DOI

24
Goldman RD, Shumaker DK, Erdos MR, Eriksson M, Goldman AE, Gordon LB, Gruenbaum Y, Khuon S, Mendez M, Varga R (2004) Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci USA 101:8963–8968

DOI

25
Gonzalo S, Kreienkamp R (2015) DNA repair defects and genome instability in Hutchinson-Gilford progeria syndrome. Curr Opin Cell Biol 34:75–83

DOI

26
Hansen NW, Hansen AJ, Sams A (2017) The endothelial border to health: mechanistic evidence of the hyperglycemic culprit of inflammatory disease acceleration. IUBMB Life 69:148–161

DOI

27
Harhouri K, Navarro C, Depetris D, Mattei MG, Nissan X, Cau P, De Sandre-Giovannoli A, Levy N (2017) MG132-induced progerin clearance is mediated by autophagy activation and splicing regulation. EMBO Mol Med 9:1294–1313

DOI

28
Hennekam RC (2006) Hutchinson-Gilford progeria syndrome: review of the phenotype. Am J Med Genet Part A 140:2603–2624

DOI

29
Hoshino A, Chiba H, Nagai K, Ishii G, Ochiai A (2008) Human vascular adventitial fibroblasts contain mesenchymal stem/progenitor cells. Biochem Biophys Res Commun 368:305–310

DOI

30
Kinoshita D, Nagasawa A, Shimizu I, Ito TK, Yoshida Y, Tsuchida M, Iwama A, Hayano T, Minamino T (2017) Progerin impairs vascular smooth muscle cell growth via the DNA damage response pathway. Oncotarget 8:34045–34056

DOI

31
Kramann R, Goettsch C,Wongboonsin J, Iwata H, Schneider RK, Kuppe C, Kaesler N, Chang-Panesso M, Machado FG, Gratwohl S (2016) Adventitial MSC-like cells are progenitors of vascular smooth muscle cells and drive vascular calcification in chronic kidney disease. Cell Stem Cell 19:628–642

DOI

32
Kubben N, Zhang W, Wang L, Voss TC, Yang J, Qu J, Liu GH, Misteli T (2016) Repression of the antioxidant NRF2 pathway in premature aging. Cell 165:1361–1374

DOI

33
Kudlow BA, Kennedy BK, Monnat RJ Jr (2007) Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nat Rev Mol Cell Biol 8:394–404

DOI

34
Lepperdinger G (2011) Inflammation and mesenchymal stem cell aging. Curr Opin Immunol 23:518–524

DOI

35
Li Y, Zhang W, Chang L, Han Y, Sun L, Gong X, Tang H, Liu Z, Deng H, Ye Y (2016) Vitamin C alleviates aging defects in a stem cell model for Werner syndrome. Protein Cell 7:478–488

DOI

36
Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM, Chau PY, Chen DJ (2005) Genomic instability in laminopathy-based premature aging. Nat Med 11:780–785

DOI

37
Liu GH, Barkho BZ, Ruiz S, Diep D, Qu J, Yang SL, Panopoulos AD, Suzuki K, Kurian L, Walsh C (2011a) Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome. Nature 472:221–225

DOI

38
Liu GH, Ding Z, Izpisua Belmonte JC (2012) iPSC technology to study human aging and aging-related disorders. Curr Opin Cell Biol 24:765–774

DOI

39
Liu GH, Suzuki K, Li M, Qu J, Montserrat N, Tarantino C, Gu Y, Yi F, Xu X, Zhang W(2014) Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs. Nat Commun 5:4330

DOI

40
Liu GH, Suzuki K, Qu J, Sancho-Martinez I, Yi F, Li M, Kumar S, Nivet E, Kim J, Soligalla RD (2011b) Targeted gene correction of laminopathy-associated LMNA mutations in patientspecific iPSCs. Cell Stem Cell 8:688–694

DOI

41
Lo Cicero A, Nissan X (2015) Pluripotent stem cells to model Hutchinson-Gilford progeria syndrome (HGPS): current trends and future perspectives for drug discovery. Ageing Res Rev 24:343–348

DOI

42
Lo CY, Tjong YW, Ho JC, Siu CW, Cheung SY, Tang NL, Yu S, Tse HF, Yao X (2014) An upregulation in the expression of vanilloid transient potential channels 2 enhances hypotonicity-induced cytosolic Ca(2)(+) rise in human induced pluripotent stem cell model of Hutchinson-Gillford progeria. PLoS ONE 9:e87273

DOI

43
Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217

DOI

44
Luo YB, Mastaglia FL, Wilton SD (2014) Normal and aberrant splicing of LMNA. J Med Genet 51:215–223

DOI

45
Mallampalli MP, Huyer G, Bendale P, Gelb MH, Michaelis S (2005) Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci USA 102:14416–14421

DOI

46
Marofi F, Vahedi G, Biglari A, Esmaeilzadeh A, Athari SS (2017) Mesenchymal stromal/stem cells: a new era in the cell-based targeted gene therapy of cancer. Front Immunol 8:1770

DOI

47
Mazereeuw-Hautier J, Wilson LC, Mohammed S, Smallwood D, Shackleton S, Atherton DJ, Harper JI (2007) Hutchinson-Gilford progeria syndrome: clinical findings in three patients carrying the G608G mutation in LMNA and review of the literature. Br J Dermatol 156:1308–1314

DOI

48
McClintock D, Gordon LB, Djabali K (2006) Hutchinson-Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-Lamin A G608G antibody. Proc Natl Acad Sci USA 103:2154–2159

DOI

49
Miller JD, Ganat YM, Kishinevsky S, Bowman RL, Liu B, Tu EY, Mandal PK, Vera E, Shim JW, Kriks S (2013) Human iPSCbased modeling of late-onset disease via progerin-induced aging. Cell Stem Cell 13:691–705

DOI

50
Miyamoto MI, Djabali K, Gordon LB (2014) Atherosclerosis in ancient humans, accelerated aging syndromes and normal aging: is lamin a protein a common link? Global Heart 9:211–218

DOI

51
Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, Liu P, Mostoslavsky G, Franco S, Murphy MM (2006) Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124:315–329

DOI

52
Muftuoglu M, Oshima J, von Kobbe C, Cheng WH, Leistritz DF, Bohr VA (2008) The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis. Hum Genet 124:369–377

DOI

53
Murfuni I, De Santis A, Federico M, Bignami M, Pichierri P, Franchitto A (2012) Perturbed replication induced genome wide or at common fragile sites is differently managed in the absence of WRN. Carcinogenesis 33:1655–1663

DOI

54
Musich PR, Zou Y (2011) DNA-damage accumulation and replicative arrest in Hutchinson-Gilford progeria syndrome. Biochem Soc Trans 39:1764–1769

DOI

55
Olive M, Harten I, Mitchell R, Beers JK, Djabali K, Cao K, Erdos MR, Blair C, Funke B, Smoot L (2010) Cardiovascular pathology in Hutchinson-Gilford progeria: correlation with the vascular pathology of aging. Arterioscler Thromb Vasc Biol 30:2301–2309

DOI

56
Oshima J, Sidorova JM, Monnat RJ Jr (2017) Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev 33:105–114

DOI

57
Pan H, Guan D, Liu X, Li J, Wang L, Wu J, Zhou J, Zhang W, Ren R, Zhang W (2016) SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Cell Res 26:190–205

DOI

58
Pasquinelli G, Tazzari PL, Vaselli C, Foroni L, Buzzi M, Storci G, Alviano F, Ricci F, Bonafe M, Orrico C (2007) Thoracic aortas from multiorgan donors are suitable for obtaining resident angiogenic mesenchymal stromal cells. Stem Cells 25:1627–1634

DOI

59
Ragnauth CD, Warren DT, Liu Y, McNair R, Tajsic T, Figg N, Shroff R, Skepper J, Shanahan CM (2010) Prelamin A acts to accelerate smooth muscle cell senescence and is a novel biomarker of human vascular aging. Circulation 121:2200–2210

DOI

60
Ren R, Deng L, Xue Y, Suzuki K, Zhang W, Yu Y, Wu J, Sun L, Gong X, Luan H (2017a) Visualization of aging-associated chromatin alterations with an engineered TALE system. Cell Res 27:483–504

DOI

61
Ren R, Ocampo A, Liu GH, Izpisua Belmonte JC (2017b) Regulation of stem cell aging by metabolism and epigenetics. Cell Metab 26:460–474

DOI

62
Ren X, Lim S, Ji Z, Yuh J, Peng V, Smith MT, Zhang L (2011) Comparison of proliferation and genomic instability responses to WRN silencing in hematopoietic HL60 and TK6 cells. PLoS ONE 6:e14546

DOI

63
Saha B, Cypro A, Martin GM, Oshima J (2014) Rapamycin decreases DNA damage accumulation and enhances cell growth of WRN-deficient human fibroblasts. Aging Cell 13:573–575

DOI

64
Scaffidi P, Misteli T (2006) Lamin A-dependent nuclear defects in human aging. Science 312:1059–1063

DOI

65
Seki M, Otsuki M, Ishii Y, Tada S, Enomoto T (2008) RecQ family helicases in genome stability: lessons from gene disruption studies in DT40 cells. Cell Cycle 7:2472–2478

DOI

66
Shamanna RA, Croteau DL, Lee JH, Bohr VA (2017) Recent advances in understanding werner syndrome. F1000Research 6:1779

DOI

67
Sturtzel C (2017) Endothelial cells. Advances in experimental medicine and biology. Can Med Assoc J 1003:71–91

68
Tiku V, Jain C, Raz Y (2016) Small nucleoli are a cellular hallmark of longevity. Nat Commun 8:16083

DOI

69
Toth JI, Yang SH, Qiao X, Beigneux AP, Gelb MH, Moulson CL, Miner JH, Young SG, Fong LG (2005) Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes. Proc Natl Acad Sci USA 102:12873–12878

DOI

70
Uccelli A, Moretta L, Pistoia V (2008) Mesenchymal stem cells in health and disease. Nat Rev Immunol 8:726–736

DOI

71
Verstraeten VL, Ji JY, Cummings KS, Lee RT, Lammerding J (2008) Increased mechanosensitivity and nuclear stiffness in Hutchinson-Gilford progeria cells: effects of farnesyltransferase inhibitors. Aging Cell 7:383–393

DOI

72
Vidak S, Foisner R (2016) Molecular insights into the premature aging disease progeria. Histochem Cell Biol 145:401–417

DOI

73
Wang C, Jurk D, Maddick M, Nelson G, Martin-Ruiz C, von Zglinicki T (2009) DNA damage response and cellular senescence in tissues of aging mice. Aging Cell 8:311–323

DOI

74
Wang L, Yi F, Fu L, Yang J, Wang S, Wang Z, Suzuki K, Sun L, Xu X, Yu Y (2017) CRISPR/Cas9-mediated targeted gene correction in amyotrophic lateral sclerosis patient iPSCs. Protein Cell 8:365–378

DOI

75
Wang S, Hu B, Ding Z, Dang Y, Wu J, Li D, Liu X, Xiao B, Zhang W, Ren R (2018) ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells. Cell Discov 4:2

DOI

76
Yang J, Li J, Suzuki K, Liu X, Wu J, Zhang W, Ren R, Zhang W, Chan P, Izpisua Belmonte JC(2017) Genetic enhancement in cultured human adult stem cells conferred by a single nucleotide recoding. Cell Res 27:1178–1181

DOI

77
Yang SH, Bergo MO, Toth JI, Qiao X, Hu Y, Sandoval S, Meta M, Bendale P, Gelb MH, Young SG(2005) Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation. Proc Natl Acad Sci USA 102:10291–10296

DOI

78
Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S (1996) Positional cloning of the Werner’s syndrome gene. Science 272:258–262

DOI

79
Zhang J, Lian Q, Zhu G, Zhou F, Sui L, Tan C, Mutalif RA, Navasankari R, Zhang Y, Tse HF (2011) A human iPSC model of Hutchinson Gilford progeria reveals vascular smooth muscle and mesenchymal stem cell defects. Cell Stem Cell 8:31–45

DOI

80
Zhang W, Li J, Suzuki K, Qu J, Wang P, Zhou J, Liu X, Ren R, Xu X, Ocampo A (2015) Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science 348:1160–1163

DOI

81
Zhang W, Qu J, Suzuki K, Liu GH, Izpisua Belmonte JC (2013) Concealing cellular defects in pluripotent stem cells. Trends in cell biology 23:587–592

DOI

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