PROGRESS IN MESENCHYMAL STEM CELLS AGING_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

YANGHaitang ,  ZHAOHeng

Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 200030, P. R. China;

Corresponding author：

ZHAOHeng, Email: h_zhao28@hotmail.com

Keywords：

Tissue engineering; Mesenchymal stem cells; Cell aging; Telomere

DOI：

10.7507/1002-1892.20140226

Video：

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Objective To comprehensively analyze the recent advancements in the field of mesenchymal stem cells (MSCs) aging,and summary its achievements and its difficulty at the present. Methods The literature about MSCs aging was reviewed and analyzed. Results Inducible telomerase reactivation of MSCs is successful to extend the life span of senescent cells,but it also has potential safety hazard.The age range presented in the research of age-related cell senescence is inconsistent,resulting in different outcomes.Many ways to improve cell in vitro culture conditions will help delay aging.Recent research indicates that oxidative stress theory is seemed to not completely explain cell aging. Conclusion Further research of MSCs aging mechanism will help the tissue engineering transform to clinical application.

Citation： YANGHaitang, ZHAOHeng. PROGRESS IN MESENCHYMAL STEM CELLS AGING. Chinese Journal of Reparative and Reconstructive Surgery, 2014, 28(8): 1037-1042. doi: 10.7507/1002-1892.20140226 Copy

1.	Moussavi-Harami F,Duwayri Y,Martin JA,et al.Oxygen effects on senescence in chondrocytes and mesenchymal stem cells:consequences for tissue engineering.Iowa Orthop J,2004,24:15-20.
2.	陈光平,罗盛康,汪海滨,等.人脂肪组织来源干细胞体外增殖分化中端粒酶的表达.中华整形外科杂志,2010,26(1):48-52.
3.	Jeon BG,Kumar BM,Kang EJ,et al.Characterization and comparison of telomere length,telomerase and reverse transcriptase activity and gene expression in human mesenchymal stem cells and cancer cells of various origins.Cell Tissue Res,2011,345(1):149-161.
4.	Baxter MA,Wynn RF,Jowitt SN,et al.Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion.Stem Cells,2004,22(5):675-682.
5.	Bonab MM,Alimoghaddam K,Talebian F,et al.Aging of mesenchymal stem cell in vitro.BMC Cell Biol,2006,7:14.
6.	Banfi A,Bianchi G,Notaro R,et al.Replicative aging and gene expression in long-term cultures of human bone marrow stromal cells.Tissue Eng,2002,8(6):901-910.
7.	Jaskelioff M,Muller FL,Paik JH,et al.Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice.Nature,2011,469(7328):102-106.
8.	Bernardes de Jesus B,Vera E,Schneeberger K,et al.Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer.EMBO Mol Med,2012,4(8):691-704.
9.	Zhao Z,Liao L,Cao Y,et al.Establishment and properties of fetal dermis-derived mesenchymal stem cell lines:plasticity in vitro and hematopoietic protection in vivo.Bone Marrow Transplant,2005,36(4):355-365.
10.	Milyavsky M,Shats I,Erez N,et al.Prolonged culture of telomerase-immortalized human fibroblasts leads to a premalignant phenotype.Cancer Res,2003,63(21):7147-7157.
11.	Burns JS,Abdallah BM,Guldberg P,et al.Tumorigenic heterogeneity in cancer stem cells evolved from long-term cultures of telomerase-immortalized human mesenchymal stem cells.Cancer Res,2005,65(8):3126-3135.
12.	Stolzing A,Jones E,McGonagle D,et al.Age-related changes in human bone marrow-derived mesenchymal stem cells:consequences for cell therapies.Mech Ageing Dev,2008,129(3):163-173.
13.	Ryu E,Hong S,Kang J,et al.Identification of senescence-associated genes in human bone marrow mesenchymal stem cells.Biochem Biophys Res Commun,2008,371(3):431-436.
14.	Shibata KR,Aoyama T,Shima Y,et al.Expression of the p16INK4A gene is associated closely with senescence of human mesenchymal stem cells and is potentially silenced by DNA methylation during in vitro expansion.Stem Cells,2007,25(9):2371-2382.
15.	Schallmoser K,Bartmann C,Rohde E et al.Replicative senescence-associated gene expression changes in mesenchymal stromal cells are similar under different culture conditions.Haematologica,2010,95(6):867-874.
16.	Yoo JK,Choi SJ,Kim JK.Expression profiles of subtracted mRNAs during cellular senescence in human mesenchymal stem cells derived from bone marrow.Exp Gerontol,2013,48(5):464-471.
17.	宁雪,李栋,汪大琨,等.脐带间充质干细胞体外衰老过程中生物学特性及基因表达谱的变化.中国实验血液学杂志,2012,20(2):458-465.
18.	Zheng Y,He L,Wan Y,et al.H3K9me-enhanced DNA hypermethylation of the p16INK4a gene:an epigenetic signature for spontaneous transformation of rat mesenchymal stem cells.Stem Cells Dev,2013,22(2):256-267.
19.	Zhang DY,Pan Y,Zhang C,et al.Wnt/beta-catenin signaling induces the aging of mesenchymal stem cells through promoting the ROS production.Mol Cell Biochem,2013,374(1-2):13-20.
20.	Squillaro T,Alessio N,Cipollaro M,et al.Partial silencing of methyl cytosine protein binding 2 (MECP2) in mesenchymal stem cells induces senescence with an increase in damaged DNA.FASEB J,2010,24(5):1593-1603.
21.	Schellenberg A,Lin Q,Schuler H,et al.Replicative senescence of mesenchymal stem cells causes DNA-methylation changes which correlate with repressive histone marks.Aging (Albany NY),2011,3(9):873-888.
22.	Bork S,Pfister S,Witt H,et al.DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells.Aging Cell,2010,9(1):54-63.
23.	Koch CM,Reck K,Shao K,et al.Pluripotent stem cells escape from senescence-associated DNA methylation changes.Genome Res,2013,23(2):248-259.
24.	Peleg S,Sananbenesi F,Zovoilis A,et al.Altered histone acetylation is associated with age-dependent memory impairment in mice.Science,2010,328(5979):753-756.
25.	Justesen J,Stenderup K,Eriksen EF,et al.Maintenance of osteoblastic and adipocytic differentiation potential with age and osteoporosis in human marrow stromal cell cultures.Calcif Tissue Int,2002,71(1):36-44.
26.	Yamada T,Akamatsu H,Hasegawa S,et al.Age-related changes of p75 neurotrophin receptor-positive adipose-derived stem cells.J Dermatol Sci,2010,58(1):36-42.
27.	Alt EU,Senst C,Murthy SN,et al.Aging alters tissue resident mesenchymal stem cell properties.Stem Cell Res,2012,8(2):215-225.
28.	Zaim M,Zaim M,Karaman S,et al.Donor age and long-term culture affect differentiation and proliferation of human bone marrow mesenchymal stem cells.Ann Hematol,2012,91(8):1175-1186.
29.	Stoeltzing O.Role of hypoxia-inducible factor 1alpha in gastric cancer cell growth,angiogenesis,and vessel maturation.J Natl Cancer Inst,2004,96(12):946-956.
30.	Harrison JS,McCarty MF,Wey JS,et al.Oxygen saturation in the bone marrow of healthy volunteers.Blood,2002,99(1):394-394.
31.	Brandl A,Meyer M,Bechmann V,et al.Oxidative stress induces senescence in human mesenchymal stem cells.Exp Cell Res,2011,317(11):1541-1547.
32.	Jin Y,Kato T,Furu M,et al.Mesenchymal stem cells cultured under hypoxia escape from senescence via down-regulation of p16 and extracellular signal regulated kinase.Biochem Biophys Res Commun,2010,391(3):1471-1476.
33.	Tsai CC,Chen YJ,Yew TL,et al.Hypoxia inhibits senescence and maintains mesenchymal stem cell properties through down-regulation of E2A-p21 by HIF-TWIST.Blood,2011,117(2):459-469.
34.	Pattappa G,Thorpe SD,Jegard NC,et al.Continuous and uninterrupted oxygen tension influences the colony formation and oxidative metabolism of human mesenchymal stem cells.Tissue engineering:Part C Methods,2013,19(1):68-79.
35.	Malladi P,Xu Y,Chiou M,et al.Effect of reduced oxygen tension on chondrogenesis and osteogenesis in adipose-derived mesenchymal cells.Am J Physiol Cell Physiol,2006,290(4):C1139-1146.
36.	Fehrer C,Brunauer R,Laschober G,et al.Reduced oxygen tension attenuates differentiation capacity of human mesenchymal stem cells and prolongs their lifespan.Aging Cell,2007,6(6):745-757.
37.	Taub J,Lau JF,Ma C,et al.A cytosolic catalase is needed to extend adult lifespan in C.elegans daf-C and clk-1 mutants.Nature,2003,421(6924):764.
38.	Svensson MJ,Larsson J.Thioredoxin-2 affects lifespan and oxidative stress in Drosophila.Hereditas,2007,144(1):25-32.
39.	Radyuk SN,Michalak K,Klichko VI,et al.Peroxiredoxin 5 confers protection against oxidative stress and apoptosis and also promotes longevity in Drosophila.Biochem J,2009,419(2):437-445.
40.	谢健,童培建,单乐天,等.H2O2氧化应激诱导兔椎间盘髓核细胞衰老的研究.中国骨伤,2013,26(4):332-335.
41.	Lin TM,Tsai JL,Lin SD,et al.Accelerated growth and prolonged lifespan of adipose tissue-derived human mesenchymal stem cells in a medium using reduced calcium and antioxidants.Stem Cells Dev,2005,14(1):92-102.
42.	Monickaraj F,Aravind S,Nandhini P,et al.Accelerated fat cell aging links oxidative stress and insulin resistance in adipocytes.J Biosci,2013,38(1):113-122.
43.	Gambino V,Michele D,Venezia GO,et al.Oxidative stress activates a specific p53 transcriptional response that regulates cellular senescence and aging.Aging Cell,2013,12(3):435-445.
44.	Supanji,Shimomachi M,Hasan MZ,et al.HtrA1 is induced by oxidative stress and enhances cell senescence through p38 MAPK pathway.Exp Eye Res,2013,112:79-92.
45.	Zhang Y,Ikeno Y,Qi W,et al.Mice deficient in both Mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity.J Gerontol A Biol Sci Med Sci,2009,64(12):1212-1220.
46.	Ho PJ,Yen ML,Tang BC,et al.H2O2 accumulation mediates differentiation capacity alteration,but not proliferative decline,in senescent human fetal mesenchymal stem cells.Antioxid Redox Signal,2013,18(15):1895-1905.
47.	Ito T.FGF-2 suppresses cellular senescence of human mesenchymal stem cells by down-regulation of TGF-beta2.Biochem Biophys Res Commun,2007,359(1):108-114.
48.	Takahashi H,Toyoda M,Birumachi J,et al.Shortening of human cell life span by induction of p16ink4a through the platelet-derived growth factor receptor beta.J Cell Physiol,2009,221(2):335-342.
49.	Stolzing A,Coleman N,Scutt A.Glucose-induced replicative senescence in mesenchymal stem cells.Rejuvenation Res,2006,9(1):31-35.
50.	Lo T,Ho JH,Yang MH,et al.Glucose reduction prevents replicative senescence and increases mitochondrial respiration in human mesenchymal stem cells.Cell Transplant,2011,20(6):813-825.

1. Moussavi-Harami F,Duwayri Y,Martin JA,et al.Oxygen effects on senescence in chondrocytes and mesenchymal stem cells:consequences for tissue engineering.Iowa Orthop J,2004,24:15-20.
2. 陈光平,罗盛康,汪海滨,等.人脂肪组织来源干细胞体外增殖分化中端粒酶的表达.中华整形外科杂志,2010,26(1):48-52.
3. Jeon BG,Kumar BM,Kang EJ,et al.Characterization and comparison of telomere length,telomerase and reverse transcriptase activity and gene expression in human mesenchymal stem cells and cancer cells of various origins.Cell Tissue Res,2011,345(1):149-161.
4. Baxter MA,Wynn RF,Jowitt SN,et al.Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion.Stem Cells,2004,22(5):675-682.
5. Bonab MM,Alimoghaddam K,Talebian F,et al.Aging of mesenchymal stem cell in vitro.BMC Cell Biol,2006,7:14.
6. Banfi A,Bianchi G,Notaro R,et al.Replicative aging and gene expression in long-term cultures of human bone marrow stromal cells.Tissue Eng,2002,8(6):901-910.
7. Jaskelioff M,Muller FL,Paik JH,et al.Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice.Nature,2011,469(7328):102-106.
8. Bernardes de Jesus B,Vera E,Schneeberger K,et al.Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer.EMBO Mol Med,2012,4(8):691-704.
9. Zhao Z,Liao L,Cao Y,et al.Establishment and properties of fetal dermis-derived mesenchymal stem cell lines:plasticity in vitro and hematopoietic protection in vivo.Bone Marrow Transplant,2005,36(4):355-365.
10. Milyavsky M,Shats I,Erez N,et al.Prolonged culture of telomerase-immortalized human fibroblasts leads to a premalignant phenotype.Cancer Res,2003,63(21):7147-7157.
11. Burns JS,Abdallah BM,Guldberg P,et al.Tumorigenic heterogeneity in cancer stem cells evolved from long-term cultures of telomerase-immortalized human mesenchymal stem cells.Cancer Res,2005,65(8):3126-3135.
12. Stolzing A,Jones E,McGonagle D,et al.Age-related changes in human bone marrow-derived mesenchymal stem cells:consequences for cell therapies.Mech Ageing Dev,2008,129(3):163-173.
13. Ryu E,Hong S,Kang J,et al.Identification of senescence-associated genes in human bone marrow mesenchymal stem cells.Biochem Biophys Res Commun,2008,371(3):431-436.
14. Shibata KR,Aoyama T,Shima Y,et al.Expression of the p16INK4A gene is associated closely with senescence of human mesenchymal stem cells and is potentially silenced by DNA methylation during in vitro expansion.Stem Cells,2007,25(9):2371-2382.
15. Schallmoser K,Bartmann C,Rohde E et al.Replicative senescence-associated gene expression changes in mesenchymal stromal cells are similar under different culture conditions.Haematologica,2010,95(6):867-874.
16. Yoo JK,Choi SJ,Kim JK.Expression profiles of subtracted mRNAs during cellular senescence in human mesenchymal stem cells derived from bone marrow.Exp Gerontol,2013,48(5):464-471.
17. 宁雪,李栋,汪大琨,等.脐带间充质干细胞体外衰老过程中生物学特性及基因表达谱的变化.中国实验血液学杂志,2012,20(2):458-465.
18. Zheng Y,He L,Wan Y,et al.H3K9me-enhanced DNA hypermethylation of the p16INK4a gene:an epigenetic signature for spontaneous transformation of rat mesenchymal stem cells.Stem Cells Dev,2013,22(2):256-267.
19. Zhang DY,Pan Y,Zhang C,et al.Wnt/beta-catenin signaling induces the aging of mesenchymal stem cells through promoting the ROS production.Mol Cell Biochem,2013,374(1-2):13-20.
20. Squillaro T,Alessio N,Cipollaro M,et al.Partial silencing of methyl cytosine protein binding 2 (MECP2) in mesenchymal stem cells induces senescence with an increase in damaged DNA.FASEB J,2010,24(5):1593-1603.
21. Schellenberg A,Lin Q,Schuler H,et al.Replicative senescence of mesenchymal stem cells causes DNA-methylation changes which correlate with repressive histone marks.Aging (Albany NY),2011,3(9):873-888.
22. Bork S,Pfister S,Witt H,et al.DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells.Aging Cell,2010,9(1):54-63.
23. Koch CM,Reck K,Shao K,et al.Pluripotent stem cells escape from senescence-associated DNA methylation changes.Genome Res,2013,23(2):248-259.
24. Peleg S,Sananbenesi F,Zovoilis A,et al.Altered histone acetylation is associated with age-dependent memory impairment in mice.Science,2010,328(5979):753-756.
25. Justesen J,Stenderup K,Eriksen EF,et al.Maintenance of osteoblastic and adipocytic differentiation potential with age and osteoporosis in human marrow stromal cell cultures.Calcif Tissue Int,2002,71(1):36-44.
26. Yamada T,Akamatsu H,Hasegawa S,et al.Age-related changes of p75 neurotrophin receptor-positive adipose-derived stem cells.J Dermatol Sci,2010,58(1):36-42.
27. Alt EU,Senst C,Murthy SN,et al.Aging alters tissue resident mesenchymal stem cell properties.Stem Cell Res,2012,8(2):215-225.
28. Zaim M,Zaim M,Karaman S,et al.Donor age and long-term culture affect differentiation and proliferation of human bone marrow mesenchymal stem cells.Ann Hematol,2012,91(8):1175-1186.
29. Stoeltzing O.Role of hypoxia-inducible factor 1alpha in gastric cancer cell growth,angiogenesis,and vessel maturation.J Natl Cancer Inst,2004,96(12):946-956.
30. Harrison JS,McCarty MF,Wey JS,et al.Oxygen saturation in the bone marrow of healthy volunteers.Blood,2002,99(1):394-394.
31. Brandl A,Meyer M,Bechmann V,et al.Oxidative stress induces senescence in human mesenchymal stem cells.Exp Cell Res,2011,317(11):1541-1547.
32. Jin Y,Kato T,Furu M,et al.Mesenchymal stem cells cultured under hypoxia escape from senescence via down-regulation of p16 and extracellular signal regulated kinase.Biochem Biophys Res Commun,2010,391(3):1471-1476.
33. Tsai CC,Chen YJ,Yew TL,et al.Hypoxia inhibits senescence and maintains mesenchymal stem cell properties through down-regulation of E2A-p21 by HIF-TWIST.Blood,2011,117(2):459-469.
34. Pattappa G,Thorpe SD,Jegard NC,et al.Continuous and uninterrupted oxygen tension influences the colony formation and oxidative metabolism of human mesenchymal stem cells.Tissue engineering:Part C Methods,2013,19(1):68-79.
35. Malladi P,Xu Y,Chiou M,et al.Effect of reduced oxygen tension on chondrogenesis and osteogenesis in adipose-derived mesenchymal cells.Am J Physiol Cell Physiol,2006,290(4):C1139-1146.
36. Fehrer C,Brunauer R,Laschober G,et al.Reduced oxygen tension attenuates differentiation capacity of human mesenchymal stem cells and prolongs their lifespan.Aging Cell,2007,6(6):745-757.
37. Taub J,Lau JF,Ma C,et al.A cytosolic catalase is needed to extend adult lifespan in C.elegans daf-C and clk-1 mutants.Nature,2003,421(6924):764.
38. Svensson MJ,Larsson J.Thioredoxin-2 affects lifespan and oxidative stress in Drosophila.Hereditas,2007,144(1):25-32.
39. Radyuk SN,Michalak K,Klichko VI,et al.Peroxiredoxin 5 confers protection against oxidative stress and apoptosis and also promotes longevity in Drosophila.Biochem J,2009,419(2):437-445.
40. 谢健,童培建,单乐天,等.H2O2氧化应激诱导兔椎间盘髓核细胞衰老的研究.中国骨伤,2013,26(4):332-335.
41. Lin TM,Tsai JL,Lin SD,et al.Accelerated growth and prolonged lifespan of adipose tissue-derived human mesenchymal stem cells in a medium using reduced calcium and antioxidants.Stem Cells Dev,2005,14(1):92-102.
42. Monickaraj F,Aravind S,Nandhini P,et al.Accelerated fat cell aging links oxidative stress and insulin resistance in adipocytes.J Biosci,2013,38(1):113-122.
43. Gambino V,Michele D,Venezia GO,et al.Oxidative stress activates a specific p53 transcriptional response that regulates cellular senescence and aging.Aging Cell,2013,12(3):435-445.
44. Supanji,Shimomachi M,Hasan MZ,et al.HtrA1 is induced by oxidative stress and enhances cell senescence through p38 MAPK pathway.Exp Eye Res,2013,112:79-92.
45. Zhang Y,Ikeno Y,Qi W,et al.Mice deficient in both Mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity.J Gerontol A Biol Sci Med Sci,2009,64(12):1212-1220.
46. Ho PJ,Yen ML,Tang BC,et al.H2O2 accumulation mediates differentiation capacity alteration,but not proliferative decline,in senescent human fetal mesenchymal stem cells.Antioxid Redox Signal,2013,18(15):1895-1905.
47. Ito T.FGF-2 suppresses cellular senescence of human mesenchymal stem cells by down-regulation of TGF-beta2.Biochem Biophys Res Commun,2007,359(1):108-114.
48. Takahashi H,Toyoda M,Birumachi J,et al.Shortening of human cell life span by induction of p16ink4a through the platelet-derived growth factor receptor beta.J Cell Physiol,2009,221(2):335-342.
49. Stolzing A,Coleman N,Scutt A.Glucose-induced replicative senescence in mesenchymal stem cells.Rejuvenation Res,2006,9(1):31-35.
50. Lo T,Ho JH,Yang MH,et al.Glucose reduction prevents replicative senescence and increases mitochondrial respiration in human mesenchymal stem cells.Cell Transplant,2011,20(6):813-825.

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