title: Intra-subject variability in human bone marrow stromal cell (BMSC) replicative senescence: molecular changes associated with BMSC senescence.
abstract: The outcomes of clinical trials using bone marrow stromal cell (BMSC) are variable; the degree of the expansion of BMSCs during clinical manufacturing may contribute to this variability since cell expansion is limited by senescence. Human BMSCs from aspirates of healthy subjects were subcultured serially until cell growth stopped. Phenotype and functional measurements of BMSCs from two subjects including senescence-associated beta-galactosidase staining and colony formation efficiency changed from an early to a senescence pattern at passage 6 or 7. Transcriptome analysis of 10 early and 15 late passage BMSC samples from 5 subjects revealed 2122 differentially expressed genes, which were associated with immune response, development, and cell proliferation pathways. Analysis of 57 serial BMSC samples from 7 donors revealed that the change from an early to senescent profile was variable among subjects and occurred prior to changes in phenotypes. BMSC age expressed as a percentage of maximum population doublings (PDs) was a good indicator for an early or senescence transcription signature but this measure of BMSC life span can only be calculated after expanding BMSCs to senescence. In order to find a more useful surrogate measure of BMSC age, we used a computational biology approach to identify a set of genes whose expression at each passage would predict elapsed age of BMSCs. A total of 155 genes were highly correlated with BMSC age. A least angle regression algorithm identified a set of 24 BMSC age-predictive genes. In conclusion, the onset of senescence-associated molecular changes was variable and preceded changes in other indicators of BMSC quality and senescence. The 24 BMSC age predictive genes will be useful in assessing the quality of clinical BMSC products.
authors: Department of Transfusion Medicine, Clinical Center, National Institutes of Health, 10 Center Dr., Bethesda, MD 20892, USA. Electronic address: renj@mail.nih.gov.
authors: Jiaqiang
authors: J
authors: Ren
authors: David F
authors: DF
authors: Stroncek
authors: Yingdong
authors: Y
authors: Zhao
authors: Ping
authors: P
authors: Jin
authors: Luciano
authors: L
authors: Castiello
authors: Sara
authors: S
authors: Civini
authors: Huan
authors: H
authors: Wang
authors: Ji
authors: J
authors: Feng
authors: Katherine
authors: K
authors: Tran
authors: Sergei A
authors: SA
authors: Kuznetsov
authors: Pamela G
authors: PG
authors: Robey
authors: Marianna
authors: M
authors: Sabatino
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D012044:Regression Analysis; D015398:Signal Transduction
chemical_list: D015415:Biomarkers
references: Rejuvenation Res. 2009 Oct;12(5):359-66
references: 19929258
references: J Embryol Exp Morphol. 1966 Dec;16(3):381-90
references: 5336210
references: PLoS One. 2008 May 21;3(5):e2213
references: 18493317
references: Haematologica. 2010 Jun;95(6):867-74
references: 20053868
references: Cell. 2008 Jun 13;133(6):1006-18
references: 18555777
references: J Exp Med. 2004 Oct 4;200(7):941-6
references: 15452179
references: J Orthop Res. 2007 Aug;25(8):1029-41
references: 17469183
references: Cancer Inform. 2007 Feb 04;3:11-7
references: 19455231
references: J Transl Med. 2012 Feb 06;10:23
references: 22309358
references: Scand J Immunol. 2003 Jan;57(1):11-20
references: 12542793
references: J Am Coll Cardiol. 2009 Dec 8;54(24):2277-86
references: 19958962
references: J Bone Miner Res. 2011 Jan;26(1):193-208
references: 20684029
references: Regen Med. 2010 Nov;5(6):933-46
references: 21082892
references: Cell. 1997 May 30;89(5):747-54
references: 9182762
references: Bone Marrow Transplant. 2002 Aug;30(4):215-22
references: 12203137
references: J Intern Med. 2007 Nov;262(5):509-25
references: 17949362
references: Haematologica. 2007 Apr;92(4):460-8
references: 17488656
references: Science. 2000 Feb 4;287(5454):860-4
references: 10657301
references: Ageing Res Rev. 2006 Feb;5(1):91-116
references: 16310414
references: J Cell Biochem. 2008 Aug 1;104(5):1865-78
references: 18404666
references: PLoS One. 2012;7(9):e45142
references: 23028809
references: Exp Neurol. 2010 May;223(1):229-37
references: 19682989
references: J Clin Oncol. 2000 Jan;18(2):307-16
references: 10637244
references: Bone. 2003 Dec;33(6):919-26
references: 14678851
references: Br J Haematol. 1999 Nov;107(2):275-81
references: 10583212
references: Cancer Inform. 2010 May 07;9:105-14
references: 20523915
references: Cancer Res. 2009 Oct 15;69(20):8200-7
references: 19826041
references: Physiol Genomics. 2009 Nov 6;39(3):210-8
references: 19723773
references: BMC Genomics. 2010 Oct 01;11:532
references: 20920304
references: PLoS Biol. 2008 Dec 2;6(12):2853-68
references: 19053174
references: Gut. 2011 Jun;60(6):788-98
references: 21257987
references: Cytotherapy. 2009;11(7):897-911
references: 19903102
references: Lancet. 2004 May 1;363(9419):1439-41
references: 15121408
references: Biotechniques. 2003 Feb;34(2):374-8
references: 12613259
references: J Biochem. 2008 Sep;144(3):399-408
references: 18550633
references: Cell. 2002 Jul 26;110(2):191-202
references: 12150927
references: Aging (Albany NY). 2011 Jul;3(7):672-84
references: 21808097
references: Cell. 2008 Jun 13;133(6):1019-31
references: 18555778
references: Cancer Res. 2007 Aug 1;67(15):7184-93
references: 17671186
references: J Neurosci. 2000 Jul 1;20(13):5083-101
references: 10864966
references: Arch Neurol. 2010 Oct;67(10):1187-94
references: 20937945
references: Nature. 2009 Jul 23;460(7254):520-4
references: 19561593
references: Exp Hematol. 2000 Jun;28(6):707-15
references: 10880757
references: Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8932-7
references: 12084934
references: Tissue Eng Part B Rev. 2010 Aug;16(4):445-53
references: 20196648
references: Stem Cells Dev. 2009 Sep;18(7):1033-42
references: 19099372
references: Stem Cell Res. 2011 May;6(3):215-25
references: 21421339
references: Rejuvenation Res. 2009 Apr;12(2):105-16
references: 19405814
references: Cells Tissues Organs. 2009;189(1-4):153-7
references: 18701807
references: J Transl Med. 2012 Oct 05;10:207
references: 23038994