Cyclic Tensile Strain Enhances Osteogenesis and Angiogenesis in Mesenchymal Stem Cells from Osteoporotic Donors
Cyclic Tensile Strain Enhances Osteogenesis and Angiogenesis in Mesenchymal Stem Cells from Osteoporotic Donors
复制标题
DOI：
10.1089/ten.tea.2013.0006
复制
发表时间：
2014-01-01
影响因子：
4.1
通讯作者：
Loboa, Elizabeth G.
中科院分区：
文献类型：
--
作者：
Charoenpanich, Adisri;Wall, Michelle E.;Loboa, Elizabeth G.
我们已经证明，10%量级的单轴循环拉伸应变促进和增强了来自正常非增生供体的人间充质干细胞（hMSC）和人脂肪源性干细胞（hASC）的成骨作用。在本研究中，分析了来自骨质疏松供体的MSC在10%单轴拉伸应变下mRNA表达的变化，以确定使用这种机械负荷范式预防和治疗骨质疏松症的潜在机制。使用超过47，000个基因探针的微阵列分析，分析了从三名绝经后骨质疏松症女性供体中分离的人MSC对机械负荷的反应。将人MSC接种在三维I型胶原构建体中以模拟骨的有机细胞外基质，并施加10%的单轴循环拉伸应变以促进骨生成。79个基因被证明是调节hMSC内从hMSC捐赠者在10%的周期性拉伸应变。通过实时定量RT-PCR进一步证实了6个基因的上调：jun D原癌基因（JUND）和纤溶酶原激活剂尿激酶受体（PLAUR），这两个基因被网络分析鉴定为潜在的关键分子;磷酸肌醇-3-激酶，催化，δ多肽（PIK 3CD）和无翅型MMTV整合位点家族，成员5 B（WNT 5 B），这两个基因在骨生物学中具有已知的重要性;以及PDZ和LIM结构域4（PDLIM 4）和血管内皮生长因子A（VEGFA），这两个基因我们先前已经显示在hASC中响应于这种机械刺激而受到显著调节。功能分析表明，10%的周期性拉伸应变诱导与细胞运动，细胞增殖和组织发育，包括在肌肉骨骼和心血管系统的发展相关的基因的表达。我们的研究结果表明，hMSC从老年人，骨质疏松的捐助者能够增强成骨分化，在10%的周期性拉伸应变与增强细胞增殖，肌肉骨骼发育和血管生成相关的基因的表达显着增加。令人惊讶的是，10%量级的周期性拉伸应变不仅增强了来自骨质疏松供体的hMSC中的骨生成，而且增强了血管生成因子的表达。更好地理解和方法，以促进成骨细胞从老年人，骨质疏松症的捐助者可能会大大有助于实现长期成功的骨再生和功能性骨组织工程，为这个不断增长的患者群体。
We have shown that the uniaxial cyclic tensile strain of magnitude 10% promotes and enhances osteogenesis of human mesenchymal stem cells (hMSC) and human adipose-derived stem cells (hASC) from normal, nonosteoporotic donors. In the present study, MSC from osteoporotic donors were analyzed for changes in mRNA expression in response to 10% uniaxial tensile strain to identify potential mechanisms underlying the use of this mechanical loading paradigm for prevention and treatment of osteoporosis. Human MSC isolated from three female, postmenopausal osteoporotic donors were analyzed for their responses to mechanical loading using microarray analysis of over 47,000 gene probes. Human MSC were seeded in three-dimensional collagen type I constructs to mimic the organic extracellular matrix of bone and 10% uniaxial cyclic tensile strain was applied to promote osteogenesis. Seventy-nine genes were shown to be regulated within hMSC from osteoporotic donors in response to 10% cyclic tensile strain. Upregulation of six genes were further confirmed with realtime RT-PCR: jun D proto-oncogene (JUND) and plasminogen activator, urokinase receptor (PLAUR), two genes identified as potential key molecules from network analysis; phosphoinositide-3-kinase, catalytic, delta polypeptide (PIK3CD) and wingless-type MMTV integration site family, member 5B (WNT5B), two genes with known importance in bone biology; and, PDZ and LIM domain 4 (PDLIM4) and vascular endothelial growth factor A (VEGFA), two genes that we have previously shown are significantly regulated in hASC in response to this mechanical stimulus. Function analysis indicated that 10% cyclic tensile strain induced expression of genes associated with cell movement, cell proliferation, and tissue development, including development in musculoskeletal and cardiovascular systems. Our results demonstrate that hMSC from aged, osteoporotic donors are capable of enhanced osteogenic differentiation in response to 10% cyclic tensile strain with significant increases in the expression of genes associated with enhanced cell proliferation, musculoskeletal development, and angiogenesis. Surprisingly, cyclic tensile strain of magnitude 10% not only enhanced osteogenesis in hMSC from osteoporotic donors, but also enhanced expression of angiogenic factors. Better understanding and methodologies to promote osteogenesis in hMSC from elderly, osteoporotic donors may greatly facilitate achieving long-term success in bone regeneration and functional bone tissue engineering for this ever-growing patient population.