Effects of shear stress on differentiation of stem cells into endothelial cells

Table 1 Studies on shear stress regulating mesenchymal stem cell to endothelial differentiation

Cell source	Condition of shear stress	Markers expressed	Function tested	Ref.
Murine embryonic mesenchymal progenitor cells	Parallel plate system 1.5 × 10-4 N/cm2 6, 12 h	CD31, vWF, and VE-cadherin	Matrigel tube formation assay, ac-LDL uptake	Wang et al[11], 2005
Canine bone marrow-derived MSCs	Pulsatile bioreactor shear stress from 1 × 10-5 to 1.5 × 10-4 N/cm2 over the course of 2 d with an additional 2 d at 1.5 × 10-4 N/cm2 of shear stress	PECAM1, VE-cadherin, and CD34	-	Dong et al[12], 2009
Human MSCs	Parallel flow chamber system 2 × 10-5 or 2 × 10-4 N/cm2 1 d, 2 d	vWF, VE-cadherin, and CD31	-	Yuan et al[13], 2013
Human MSCs	Flow-engaging system 2.5 × 10-5, 1 × 10-4 N/cm2 1 d	CD31, vWF, and VEGFR2	-	Kim et al[14], 2011
Rat bone marrow-derived MSCs	Parallel flow chamber system 1 × 10-4, 1.5 × 10-4, 2 × 10-4, 2.5 × 10-4 N/cm2 12, 24, 48 h	CD31, VEGFR-2 and t-PA	-	Bai et al[15], 2010
Sheep bone marrow-derived MSCs	Cyclic flexure and laminar flow bioreactor. Average fluid shear stress of 1.1505 × 10-5 N/cm2 1, 3 w	CD31 and vWF	-	Engelmayr et al[16], 2006
Rat bone marrow-derived MSCs	Unique experimental protocol 2 × 10-4 N/cm2 laminar shear stress and 120/80 mmHg cyclic pressure at 1 Hz 5 d	CD133, vWF, E-selectin, and PECAM1	-	Maul et al[17], 2011
Human MSCs	Bioreactor system 2.5 × 10-5 N/cm2 stress followed by 3% circumferential stretch for 3 d, and an additional 5% circumferential stretch for 4 d	Flk-1, vWF, E-selectin, and VE-cadherin	-	Kim et al[18], 2016
Rat bone marrow-derived MSCs	Orbital shaker 2 × 10-5, 5 × 10-5, 1 × 10-4 N/cm2 6, 12, 24 h	CD34, Cadherin5, and vWF	Matrigel tube formation assay	Homayouni Moghadam et al[19], 2014
Human exfoliated deciduous teeth (SHEDs)	cultured with or without VEGF (50 ng/mL) for 12 h 6 × 10-5, 1.2 × 10-4 N/cm2 4, 8 and 12 h	VEGF, VEGFR2, DLL4, Notch1, EphrinB2, Hey1 and Hey2	In vitro Matrigel angiogenesis assay	Wang et al[20], 2018
Rat bone marrow-derived MSCs	under normoxia or hypoxia 1.2 × 10-4 N/cm2 24 h	CXCR4, phosphorylated Akt and VEGFA	-	Liu et al[21], 2017
Human ASCs	Custom-made bioreactor capable of applying both shear and tensile stresses 0-2.5 × 10-5 N/cm2 1, 2, and 7 d	Flk-1, vWF, and VE-cadherin	-	Bassaneze et al[22], 2010
Human ASCs	Parallel plate type flow chamber 1.8 × 10-4 N/cm2 5 d	PECAM1 and VE-cadherin	Tube structure formation in 3D matrices	Shojaei et al[23], 2013
Human ASCs	Orbital shaker 1.2 × 10-4 N/cm2 8 d	CD31	In vivo evaluation of the thrombogenicity, ac-LDL uptake	Fontijn et al[24], 2014
Human ASCs	Orbital shaker 1.2 × 10-4 N/cm2 7, 14 d	vWF, eNOS, Flt-1, CD31, Flk-1 and VE-cadherin	-	Fischer et al[25], 2009
Human ASCs	Perfusion bioreactor 4.5 × 10-5 N/cm2 1 d	vWF, Flk-1 and VE-cadherin	-	Hasanzadeh et al[27], 2017
Human amniotic fluid-derived MSCs	Orbital shaker 1.2 × 10-4 N/cm2 2 d	CD31 and vWF	Matrigel tube formation assay, ac-LDL uptake	Zhang et al[28], 2009
Human Placenta-derived MSCs	Parallel flow chamber system 6 × 10-5, 1.2 × 10-4 N/cm2 3, 6, 12, 24 h	Flt-1 and Flk-1	Matrigel tube formation assay, ac-LDL uptake	Wu et al[29], 2008

ac-LDL: Acetylated-low density lipoprotein LDL; CXCR4: C-X-C chemokine receptor type 4; eNOS: Endothelial nitric-oxide synthase; Flk-1: Fetal liver kinase-1; MSCs: Mesenchymal stem cells; NO: Nitric oxide; PECAM1: Platelet/endothelial cell adhesion molecule 1; PECAM1: Platelet/endothelial cell adhesion molecule 1; t-PA: Tissue-type plasminogen activator; VE-cadherin: Vascular endothelial-cadherin; VEGFR2: Vascular endothelial growth factor receptor 2; vWF: Von Willebrand factor.

Table 2 Studies on shear stress regulating endothelial progenitor cell to endothelial differentiation

Cell source	Condition of shear stress	Markers expressed	Function tested	Signaling molecule	Ref.
Human umbilical cord blood derived- EPCs	Rotating-disk-type flow-loading device Shear stress applied ranged from 1 × 10-6 to 5 × 10-5 N/cm2 1, 2 d	VEGFR1, VEGFR2, VE-cadherin, Tie2, VCAM1, integrin αv/β3, E-selectin, eNOS, matrix metalloproteinase 9, and VEGF	-	PI3K/Akt/mTOR	Obi et al[32], 2012
Human cord blood derived-EPCs	Perfusion system. Unidirectional shear stress (0.3 ± 0.1, 6 ± 3 × 10-5 N/cm2) and bidirectional shear stress (0.3 ± 3 × 10-5 N/cm2) 24 h	Tissue factor	-	-	Mazzolai et al[33], 2011
Human peripheral blood mononuclear cells-derived EPCs	Rotating disk-type flow loading device 0.1 to 2.5 × 10-5 N/cm2 24 h	Flk-1, Flt-1 and VE-cadherin	Matrigel tube formation assay	-	Yamamoto et al[34], 2003
Human blood mononuclear cells-derived EPCs	Parallel-plate coculture flow chamber 5 × 10-5 N/cm2 24 h	CD31 and vWF	-	Akt	Ye et al[35], 2008
Human CD34+ hematopoietic progenitor cells	Cone-and-plate apparatus 1.5 × 10-4 N/cm2 24 h	VEGFR2, eNOS, and a VEGFR2 promoter-driven reporter gene	-	HoxA9	Rössig et al[36], 2005
Human peripheral blood mononuclear cells-derived EPCs	Parallel plate flow chamber channel 5 × 10-5, 1.5 × 10-4 and 2.5 × 10-4 N/cm2 for 24 h or 1.5 × 10-4 N/cm2 for 5, 10 and 20 h	Phosphorylated Tie2, phosphorylated Akt andeNOS	reendothelialization assay in nude mouse model	Tie2 /PI3K/Akt	Yang et al[37], 2012
EPCs isolated from rat bone marrow	Flow chamber system 2 × 10-5, 6 × 10-5, 1.2 × 10-4, and 2 × 10-4 N/cm2 12, 24 h	CD31 and vWF	-	Integrins	Cui et al[38], 2012
Human umbilical cord blood derived- EPCs	Parallel plate flow chamber system 1.5 × 10-4 N/cm2 6, 12, and 24 h	VEGFR2, VE-cadherin, vWF, and CD31	Matrigel tube formation assay	miR-34a/Foxj2	Cheng et al[39], 2014
Human peripheral blood mononuclear cells-derived EPCs	Rotating-disk-type flow-loading device. Shear stress applied ranged from 0.1 to 5 × 10-5 N/cm2 6, 12, 24 h	EphrinB2, Notch1/3, Hey1/2, and activin receptor-like kinase 1	-	Sp1	Obi et al[41], 2009
Human peripheral blood mononuclear cells-derived EPCs	Parallel plate-type device 1.5 × 10-4 N/cm2 1 d	CD31, vWF, and ephrinB2	-	p38 and MAPK pathways	Suzuki et al[42], 2012

Akt: Protein kinase B; ALK1: Activin receptor-like kinase 1; Ac-H3: H3 acetylation; eNOS: Endothelial nitric-oxide synthase; BH4: Tetrahydrobiopterin; EPCs: Endothelial progenitor cells; Flk-1: Fetal liver kinase-1; Flt-1: Fms-like tyrosine kinase-1; Foxj2: Forkhead box j2; GTPCH: Guanosine triphosphate cyclohydrolase; KLF2: Krüppel-like factor 2; MAPK: Mitogen-activated protein kinase; miR-34a: MicroRNA-34a; PI3K: Phosphoinositide 3-kinase; PTEN: Tumor suppressor phosphatase and tensin homolog; Tie2: Tyrosine kinase with immunoglobulin and epidermal growth factor homology domain-2; VCAM1: Vascular cell adhesion molecule-1; VE-cadherin: Vascular endothelial-cadherin; VEGFR1: Vascular endothelial growth factor receptor 1; VEGFR2: Vascular endothelial growth factor receptor 2; vWF: Von Willebrand factor .

Table 3 Studies on shear stress regulating embryonic stem cell to endothelial differentiation

Cell source	Condition of shear stress	Markers expressed	Function tested	Signaling molecule	Ref.
Mouse ESCs	Cone-plate apparatus 1 × 10-4 N/cm2 1 d	VEGFR2, PECAM1, smooth muscle actin, smooth muscle protein 22-α, MEF2C, and α-sarcomeric actin	Matrigel tube formation assay	Epigenetic modification of histones and transcription complexes bearing acetyltransferase activity	Illi et al[44], 2005
Mouse ESCs	Parallel plate flow chamber 1.5 × 10-4 N/cm2 2 d	Flk-1, VE-cadherin, and PECAM1	Matrigel tube formation assay	-	Ahsan and Nerem[45], 2010
Mouse ESCs	Parallel plate flow chamber 5 × 10-5 N/cm2 2 d	Flk-1, VE-cadherin, and PECAM1	-	-	Nsiah et al[46], 2014
Mouse ESCs	Parallel plate bioreactor system 1.5 × 10-5, 5 × 10-5, and 1.5 × 10-4 N/cm2 4 d	Flk1, PECAM1, and CD41	-	Flk1	Wolfe and Ahsan[47], 2013
Mouse ESCs and Sac-1+ cells	Parallel plate flow chamber 1.2 × 10-4 N/cm2 1 d	PECAM1, CD133, VE-cadherin, VEGFR1, VEGFR2, eNOS	Matrigel tube formation assay	Flk-1-PI3K-Akt-HDAC3-p53-p21 pathway	Zeng et al[48], 2006
Mouse Flk-1+ cells	Parallel plate-type device 1.5 × 10-5 to 1 × 10-4 N/cm2 1, 2, 3 d	Flk1, Flt1, VE-cadherin, and PECAM1	Tube formation assay in collagen gel	Ligand-independent activation of Flk-1	Yamamoto et al[49], 2005
Murine ESCs–derived Flk-1+ cells	Shear stress-loading device 1 × 10-4 N/cm2 24 h	EphrinB2	-	VEGFR-Notch signaling	Noguera-Troise et al[50], 2006
Mouse CD41+c-Kit+ cells	Dynamic flow system 5 × 10-5 N/cm2 2 d	PECAM1, Runx1, Myb, and Klf2	In vivo assay	NO	Adamo et al[51], 2009
Mouse Flk1+ cells	Pulsatile flow culturing circuit. Pulsatile wall shear stress from 0.98 to 2.2 × 10-5 N/cm2 and a circumferential strain stress 0/46-0/96 N/cm2 2 d	PECAM1 and SMA	-	-	Huang et al[52], 2005
Mouse ESCs	Multiplex microfluidic array 1.6 × 10-7-1.6 × 10-4 N/cm2 3 d	Fgf5	-	HSPGs	Toh and Voldman[54], 2011
Mouse ESCs	Microfluidic culture device 1-10 mL/min 6 d	PECAM1	-	-	Lee et al[55], 2011

eNOS: Endothelial nitric-oxide synthase; ESC: Embryonic stem cells; Flk-1: Fetal liver kinase-1; Flt-1: Fms-like tyrosine kinase-1; HDAC3: Histone deacetylase 3; HSPGs: Heparan sulfate proteoglycans; MEF2C: Myocyte enhancer factor-2C; NO: Nitric oxide; PECAM1: Platelet/endothelial cell adhesion molecule 1; PI3K: Phosphoinositide 3-kinase; SMA: Smooth muscles actin; VE-cadherin: Vascular endothelial-cadherin; VEGFR1: Vascular endothelial growth factor receptor 1; VEGFR2: Vascular endothelial growth factor receptor 2; vWF: Von Willebrand factor.