Mechanical stimuli differentially control stem cell behavior: morphology, proliferation, and differentiation.
Mesenchymal stem cell (MSC) therapy has demonstrated applications in vascular regenerative medicine. Although blood vessels exist in a mechanically dynamic environment, there has been no rigorous, systematic analysis of mechanical stimulation on stem cell differentiation. We hypothesize that mechanical stimuli, relevant to the vasculature, can differentiate MSCs toward smooth muscle (SMCs) and endothelial cells (ECs). This was tested using a unique experimental platform to differentially apply various mechanical stimuli in parallel. Three forces, cyclic stretch, cyclic pressure, and laminar shear stress, were applied independently to mimic several vascular physiologic conditions. Experiments were conducted using subconfluent MSCs for 5 days and demonstrated significant effects on morphology and proliferation depending upon the type, magnitude, frequency, and duration of applied stimulation. We have defined thresholds of cyclic stretch that potentiate SMC protein expression, but did not find EC protein expression under any condition tested. However, a second set of experiments performed at confluence and aimed to elicit the temporal gene expression response of a select magnitude of each stimulus revealed that EC gene expression can be increased with cyclic pressure and shear stress in a cell-contact-dependent manner. Further, these MSCs also appear to express genes from multiple lineages simultaneously which may warrant further investigation into post-transcriptional mechanisms for controlling protein expression. To our knowledge, this is the first systematic examination of the effects of mechanical stimulation on MSCs and has implications for the understanding of stem cell biology, as well as potential bioreactor designs for tissue engineering and cell therapy applications.
Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15219, USA.
Timothy M
TM
Maul
Douglas W
DW
Chew
Alejandro
A
Nieponice
David A
DA
Vorp
D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D048430:Cell Shape / Q000235:genetics; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D010641:Phenotype; D051381:Rats; D011917:Rats, Inbred Lew; D013314:Stress, Mechanical; D013997:Time Factors
D009124:Muscle Proteins
Circ Res. 2002 Jul 12;91(1):77-82
12114325
Clin Sci (Lond). 1998 Jun;94(6):601-7
9854457
Int J Hematol. 2004 Jul;80(1):1-6
15293562
J Orthop Res. 2003 May;21(3):451-7
12706017
Nat Methods. 2010 Sep;7(9):733-6
20676108
Circ Res. 1970 Apr;26(4):507-22
5435712
Endothelium. 1997;5(2):85-93
9237042
J Biomed Mater Res A. 2008 Aug;86(2):411-9
17969030
J Orthop Res. 2004 Nov;22(6):1283-9
15475210
Science. 2005 Nov 18;310(5751):1139-43
16293750
Dev Cell. 2004 Apr;6(4):483-95
15068789
Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4478-85
11296290
Connect Tissue Res. 1989;23(2-3):123-36
2698313
Physiol Genomics. 2002 Dec 26;12(1):13-23
12419857
J Biomech. 2007;40(11):2399-405
17261311
Circ Res. 1999 Feb 19;84(3):315-22
10024305
Atherosclerosis. 2000 Dec;153(2):323-35
11164421
Exp Hematol. 2004 Dec;32(12):1238-45
15588948
Physiol Genomics. 2002 Dec 3;11(3):245-51
12388793
Biomech Model Mechanobiol. 2005 Mar;3(3):141-6
15668766
J Biomech. 2004 Dec;37(12):1923-8
15519600
Arterioscler Thromb Vasc Biol. 2004 Sep;24(9):1596-601
15231515
J Cell Physiol. 2001 Jul;188(1):132-8
11382929
Ann Biomed Eng. 2005 Jun;33(6):772-9
16078617
Med Biol Eng Comput. 1998 Jan;36(1):122-8
9614760
Vasc Med. 2004 Feb;9(1):35-45
15230487
Physiol Rev. 2004 Jul;84(3):767-801
15269336
J Cell Physiol. 1994 Jan;158(1):133-9
8263020
Exp Cell Res. 1999 Jul 10;250(1):174-86
10388531
Anat Rec A Discov Mol Cell Evol Biol. 2004 Jan;276(1):22-33
14699631
J Biomed Mater Res A. 2007 Jun 1;81(3):523-30
17133453
Biotechnol Bioeng. 2004 Nov 5;88(3):359-68
15486942
Hypertension. 2001 Sep;38(3 Pt 2):581-7
11566935
Bone. 2005 Jun;36(6):1047-55
15869916
Plant Methods. 2005 Nov 09;1(1):10
16280083
Microcirculation. 1998;5(2-3):91-4
9789249
J Mol Cell Cardiol. 2002 Oct;34(10):1345-56
12392995
Circulation. 2002 Sep 3;106(10):1199-204
12208793
Cell. 2008 Oct 17;135(2):343-54
18957207
J Cell Physiol. 1997 Mar;170(3):228-34
9066778
Arterioscler Thromb Vasc Biol. 2005 Sep;25(9):1817-23
15994439
J Biomech Eng. 1981 Aug;103(3):172-6
7278195
Ann Biomed Eng. 2003 Apr;31(4):391-402
12723680
Plant Mol Biol. 2000 Aug;43(5-6):677-90
11089869
Biomaterials. 2008 Apr;29(11):1610-9
18194813
Comp Biochem Physiol B Biochem Mol Biol. 2008 May;150(1):23-32
18302990
Biorheology. 2006;43(2):95-116
16687781
FASEB J. 1995 Jul;9(10):874-82
7615157
J Surg Res. 2002 Jan;102(1):13-21
11792146
Biochem Biophys Res Commun. 2001 Mar 23;282(1):142-7
11263983
J Biomech Eng. 2007 Feb;129(1):110-6
17227105
Ann Biomed Eng. 2000 Apr;28(4):351-62
10870892
Mol Cell Biomech. 2006 Mar;3(1):21-34
16711069
Cytokine. 2005 Jul 21;31(2):119-26
15919213
Science. 1999 Apr 2;284(5411):143-7
10102814
Stem Cells. 2001;19(3):219-25
11359947
Circ Res. 2000 Feb 4;86(2):185-90
10666414
Life Sci. 1997;61(10):987-96
9296337
J Cell Physiol. 2010 Feb;222(2):268-77
19847802
J Cell Biochem. 1997 Feb;64(2):295-312
9027589
Ann Biomed Eng. 2001 Jun;29(6):476-82
11459341
Tissue Eng. 2004 Mar-Apr;10(3-4):361-9
15165453
Dev Biol. 2001 Dec 15;240(2):404-18
11784072
Biorheology. 2005;42(6):421-41
16369082
Cell Res. 2004 Feb;14(1):16-26
15040886
Methods. 2001 Dec;25(4):402-8
11846609
Blood. 1993 Jul 1;82(1):66-76
8324235
Stem Cell Rev. 2008 Sep;4(3):137-47
18665337
Cells Tissues Organs. 2006;183(2):80-6
17053324
Biophys J. 2004 Jan;86(1 Pt 1):617-28
14695306
Am J Physiol Heart Circ Physiol. 2005 Apr;288(4):H1915-24
15576436
Surgery. 2007 Mar;141(3):394-402
17349852
Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16095-100
17060641
Tissue Eng. 2001 Dec;7(6):717-28
11749729
Annu Rev Biochem. 1988;57:375-413
2972252
Ann Biomed Eng. 2007 Sep;35(9):1585-94
17522977
Mol Cell Biol. 2003 Apr;23(7):2425-37
12640126
Invest Ophthalmol Vis Sci. 2007 Jul;48(7):3161-77
17591886
Anal Biochem. 1987 Apr;162(1):156-9
2440339