大範圍頭蓋骨缺損修復是目前骨科醫學上的一大難題。我們已經證實使用桿狀病毒搭配重組酶系統能夠成功的轉導脂肪間葉幹細胞(adipose-derived stem cell, ASC)，使其持續表現人類第二骨形態發生蛋白質(bone morphogenetic protein-2, BMP-2)，證實能夠修復大範圍腿骨缺陷，但我們卻發現以相同的系統在大範圍頭蓋骨缺陷中的修復不如預期。由於ASCs細胞本身不容易往硬骨組織分化，因此我們認為單靠BMP-2蛋白的刺激仍無法有效的修復大範圍頭蓋骨缺陷。近期有研究指出趨化因子基質細胞衍生因子1(stromal cell-derived factor 1, SDF-1)能吸引間葉幹細胞的遷移，並幫助組織的修復。因此我們假設當ASCs共同表現BMP-2與SDF-1時，能有效促進宿主間葉幹細胞遷移，並能促進頭蓋骨缺陷的修復。
本研究利用新型桿狀病毒系統促使ASCs細胞長效表現BMP-2與SDF-1，並探討共同表現BMP-2與SDF-1下是否能促進ASCs增進大範圍頭蓋骨缺陷的修復。我們先以migration assay分析在ASCs表現BMP-2與SDF-1時吸引間葉幹細胞的效率，並且確認ASCs表現SDF-1時較能夠有效的吸引間葉幹細胞的遷移。我們在骨分化指標基因與茜紅染色以及鈣沉積定量分析中，發現ASCs在表現BMP-2與SDF-1時都有較明顯的骨分化情形，並以西方點墨法與luciferase assay確認BMP-2與SDF-1分別調控Smad與MAPK/ERK路徑，因此促進ASCs往硬骨分化。我們將轉導後ASCs植入大鼠頭蓋骨缺陷模型，並看到共同表現BMP-2與SDF-1的ASCs在術後第12周約能修復大鼠頭蓋骨缺陷≈70%的骨體積以及≈74%骨密度，並在組織免疫染色中也看到共同表現BMP-2與SDF-1下有明顯的骨組織生成。本研究結合了趨化因子SDF-1與生長因子BMP-2的共同表現，提升了脂肪幹細胞的硬骨分化能力，並希望透過本研究的結果，能促進脂肪間葉幹細胞在骨組織工程臨床上的應用。

Bony defects in the craniofacial skeleton remain a challenging health concern. Our previous studies have shown that baculovirus (BV)-mediated gene therapy combined with adipose-derived mesenchymal stem cell (ASCs) to persistently express BMP-2 can improve the femoral bone defects. However, complete repair of the calvarial bone defects using the BV-mediated ASCs therapy remained difficult. Stromal cell-derived factor 1 (SDF-1) is a chemokine that can recruit mesenchymal stem cell (MSCs). Because of the inferior osteogenesis of ASCs, we hypothesized that implantation of ASCs persistently co-expressing SDF-1 and BMP-2 can recruit host MSCs and promote the osteogenic ability of ASCs, which synergistically promote calvarial bone healing. Therefore, we constructed a new Cre/loxP-based BV system encoding SDF-1 and BMP-2. Transduction of the rat ASCs with the new BV system conferred prolonged SDF-1 and BMP-2 co-expression, which recruited MSC in the transwell migration and synergistically promoted the osteogenic differentiation of transduced ASCs through Smad pathway and MAPK/ERK pathway in vitro. Furthermore, implantation of the ASCs co-expressing BMP-2/SDF-1 into critical-size (6 mm in diameter) calvarial bone defects in SD rat accelerated the bone healing, filling »70% of bone volume with native calvaria-like flat bone in 12 weeks. Altogether, this study confirmed that BV-engineered ASCs co-expressing BMP-2/SDF-1 could synergistically stimulate the ASCs osteogenesis in vitro and improve the calvarial bone healing in vivo.

摘要 3
第一章 文獻回顧 7
1-1骨組織工程簡介 7
1-1-1骨組織工程背景與國內外研究情況 7
1-1-2骨骼結構、生成與重建機制 8
1-1-3骨骼系統常見傷害 10
1-1-4大範圍頭蓋骨缺損 10
1-1-5骨組織工程的發展 11
1-2幹細胞在組織工程上的應用 12
1-3 BMP-2與SDF-1在骨組織工程上的應用與發展 13
1-4基因治療 14
1-5桿狀病毒表現系統 16
1-6 重組酶系統 18
1-7 桿狀病毒在骨組織工程的應用 19
1-8 研究動機 19
第二章 材料與方法 26
2-1重組桿狀病毒之建構與製備 26
2-1-1昆蟲細胞培養 26
2-1-2建構重組表現載體(donor plasmid) 26
2-1-3 重組表現載體之轉置反應(transposition) (Bac-to-Bac系統) 27
2-1-5 重組bacmid之轉染反應(transfection) (製備P0病毒) 28
2-1-6 基因重組桿狀病毒放大培養 28
2-1-8桿狀病毒效價測定 29
2-2大鼠脂肪間葉幹細胞之分離與培養 29
2-3桿狀病毒轉導幹細胞之策略 30
2-4酵素免疫分析法(ELISA) 31
2-5 細胞遷移實驗(Migration assay) 32
2-6即時偵測同步定量聚合酶連鎖反應分析(qRT-PCR) 33
2-7西方點墨法(Western blot analysis) 35
2-8螢光素酶報導基因分析法(Luciferase reporter assay) 36
2-9茜紅素(Alizarin Red)染色分析 37
2-10鈣沉積定量分析 38
2-11 動物頭蓋骨缺陷植入所需之細胞轉導與載體製備 38
2-12 大鼠頭蓋骨手術植入程序 38
2-13 電腦斷層掃描分析 39
2-14 H&E染色 40
2-15 組織免疫染色 40
2-16統計學分析 41
第三章 結果與討論 42
3-1 BMP-2與SDF-1在脂肪間葉幹細胞(ASCs)中表現量之分析 42
3-2 分析ASCs表現SDF-1誘導MSC遷移之效率 42
3-3 在ASCs中硬骨基因表現與硬骨分化成效之分析 43
3-4 BMP-2與SDF-1調控ASCs硬骨分化路徑之分析 44
3-5 以ASCs搭配Gelatin支架修復大鼠大範圍頭蓋骨缺陷之分析 46
3-5 組織切片染色分析頭蓋骨組織新生與組織重塑 47
3-6討論 48
參考文獻 60

Abu El-Asrar AM, Al-Kharashi SA, Missotten L, Geboes K. 2006. Expression of growth factors in the conjunctiva from patients with active trachoma. Eye (Lond) 20(3):362-9.
Ai-Aql ZS, Alagl AS, Graves DT, Gerstenfeld LC, Einhorn TA. 2008. Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res 87(2):107-18.
Airenne KJ, Makkonen KE, Mahonen AJ, Yla-Herttuala S. 2010. In vivo application and tracking of baculovirus. Curr Gene Ther 10(3):187-94.
Amini AR, Laurencin CT, Nukavarapu SP. 2012. Bone tissue engineering: recent advances and challenges. Crit Rev Biomed Eng 40(5):363-408.
Bai Y, Li P, Yin G, Huang Z, Liao X, Chen X, Yao Y. 2013. BMP-2, VEGF and bFGF synergistically promote the osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells. Biotechnol Lett 35(3):301-8.
Bishop GB, Einhorn TA. 2007. Current and future clinical applications of bone morphogenetic proteins in orthopaedic trauma surgery. Int Orthop 31(6):721-7.
Bose S, Tarafder S. 2012. Calcium phosphate ceramic systems in growth factor and drug delivery for bone tissue engineering: a review. Acta Biomater 8(4):1401-21.
Carragee EJ, Chu G, Rohatgi R, Hurwitz EL, Weiner BK, Yoon ST, Comer G, Kopjar B. 2013. Cancer risk after use of recombinant bone morphogenetic protein-2 for spinal arthrodesis. J Bone Joint Surg Am 95(17):1537-45.
Chen B, Lin H, Wang J, Zhao Y, Wang B, Zhao W, Sun W, Dai J. 2007. Homogeneous osteogenesis and bone regeneration by demineralized bone matrix loading with collagen-targeting bone morphogenetic protein-2. Biomaterials 28(6):1027-35.
Chen CY, Lin CY, Chen GY, Hu YC. 2011. Baculovirus as a gene delivery vector: recent understandings of molecular alterations in transduced cells and latest applications. Biotechnol Adv 29(6):618-31.
Chen D, Zhao M, Mundy GR. 2004. Bone morphogenetic proteins. Growth Factors 22(4):233-41.
Chen G, Deng C, Li YP. 2012. TGF-beta and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci 8(2):272-88.
Chen HC, Sung LY, Lo WH, Chuang CK, Wang YH, Lin JL, Hu YC. 2008. Combination of baculovirus-expressed BMP-2 and rotating-shaft bioreactor culture synergistically enhances cartilage formation. Gene Ther 15(4):309-17.
Cheng Z, Ou L, Zhou X, Li F, Jia X, Zhang Y, Liu X, Li Y, Ward CA, Melo LG and others. 2008. Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium improves cardiac performance. Mol Ther 16(3):571-9.
Cheshenko N, Krougliak N, Eisensmith RC, Krougliak VA. 2001. A novel system for the production of fully deleted adenovirus vectors that does not require helper adenovirus. Gene Ther 8(11):846-54.
Devine JG, Dettori JR, France JC, Brodt E, McGuire RA. 2012. The use of rhBMP in spine surgery: is there a cancer risk? Evid Based Spine Care J 3(2):35-41.
Franceschi RT, Xiao G. 2003. Regulation of the osteoblast-specific transcription factor, Runx2: responsiveness to multiple signal transduction pathways. J Cell Biochem 88(3):446-54.
Ge C, Cawthorn WP, Li Y, Zhao G, Macdougald OA, Franceschi RT. 2016. Reciprocal Control of Osteogenic and Adipogenic Differentiation by ERK/MAP Kinase Phosphorylation of Runx2 and PPARgamma Transcription Factors. J Cell Physiol 231(3):587-96.
Ge C, Xiao G, Jiang D, Yang Q, Hatch NE, Roca H, Franceschi RT. 2009. Identification and functional characterization of ERK/MAPK phosphorylation sites in the Runx2 transcription factor. J Biol Chem 284(47):32533-43.
Gong J, Meng HB, Hua J, Song ZS, He ZG, Zhou B, Qian MP. 2014. The SDF-1/CXCR4 axis regulates migration of transplanted bone marrow mesenchymal stem cells towards the pancreas in rats with acute pancreatitis. Mol Med Rep 9(5):1575-82.
Guang LG, Boskey AL, Zhu W. 2012. Regulatory role of stromal cell-derived factor-1 in bone morphogenetic protein-2-induced chondrogenic differentiation in vitro. Int J Biochem Cell Biol 44(11):1825-33.
Hankenson KD, Dishowitz M, Gray C, Schenker M. 2011. Angiogenesis in bone regeneration. Injury 42(6):556-61.
Herberg S, Kondrikova G, Periyasamy-Thandavan S, Howie RN, Elsalanty ME, Weiss L, Campbell P, Hill WD, Cray JJ. 2014a. Inkjet-based biopatterning of SDF-1beta augments BMP-2-induced repair of critical size calvarial bone defects in mice. Bone 67:95-103.
Herberg S, Susin C, Pelaez M, Howie RN, Moreno de Freitas R, Lee J, Cray JJ, Jr., Johnson MH, Elsalanty ME, Hamrick MW and others. 2014b. Low-dose bone morphogenetic protein-2/stromal cell-derived factor-1beta cotherapy induces bone regeneration in critical-size rat calvarial defects. Tissue Eng Part A 20(9-10):1444-53.
Ho YC, Chung YC, Hwang SM, Wang KC, Hu YC. 2005. Transgene expression and differentiation of baculovirus-transduced human mesenchymal stem cells. J Gene Med 7(7):860-8.
Ho YC, Lee HP, Hwang SM, Lo WH, Chen HC, Chung CK, Hu YC. 2006. Baculovirus transduction of human mesenchymal stem cell-derived progenitor cells: variation of transgene expression with cellular differentiation states. Gene Ther 13(20):1471-9.
Holloway JL, Ma H, Rai R, Hankenson KD, Burdick JA. 2015. Synergistic Effects of SDF-1alpha and BMP-2 Delivery from Proteolytically Degradable Hyaluronic Acid Hydrogels for Bone Repair. Macromol Biosci.
Hu E, Kim JB, Sarraf P, Spiegelman BM. 1996. Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma. Science 274(5295):2100-3.
Hu YC, Yao K, Wu TY. 2008. Baculovirus as an expression and/or delivery vehicle for vaccine antigens. Expert Rev Vaccines 7(3):363-71.
Huebsch N, Lippens E, Lee K, Mehta M, Koshy ST, Darnell MC, Desai RM, Madl CM, Xu M, Zhao X and others. 2015. Matrix elasticity of void-forming hydrogels controls transplanted-stem-cell-mediated bone formation. Nat Mater 14(12):1269-77.
Hwang HD, Lee JT, Koh JT, Jung HM, Lee HJ, Kwon TG. 2015. Sequential Treatment with SDF-1 and BMP-2 Potentiates Bone Formation in Calvarial Defects. Tissue Eng Part A 21(13-14):2125-35.
James AW. 2013. Review of Signaling Pathways Governing MSC Osteogenic and Adipogenic Differentiation. Scientifica (Cairo) 2013:684736.
Jin Q, Giannobile WV. 2014. SDF-1 enhances wound healing of critical-sized calvarial defects beyond self-repair capacity. PLoS One 9(5):e97035.
Jun JH, Yoon WJ, Seo SB, Woo KM, Kim GS, Ryoo HM, Baek JH. 2010. BMP2-activated Erk/MAP kinase stabilizes Runx2 by increasing p300 levels and histone acetyltransferase activity. J Biol Chem 285(47):36410-9.
Jung Y, Bauer G, Nolta JA. 2012. Concise review: Induced pluripotent stem cell-derived mesenchymal stem cells: progress toward safe clinical products. Stem Cells 30(1):42-7.
Kim BC, Kim JH. 1998. Exogenous C2-ceramide activates c-fos serum response element via Rac-dependent signalling pathway. Biochem J 330 ( Pt 2):1009-14.
Kisiel M, Klar AS, Ventura M, Buijs J, Mafina MK, Cool SM, Hilborn J. 2013. Complexation and sequestration of BMP-2 from an ECM mimetic hyaluronan gel for improved bone formation. PLoS One 8(10):e78551.
Kon T, Cho TJ, Aizawa T, Yamazaki M, Nooh N, Graves D, Gerstenfeld LC, Einhorn TA. 2001. Expression of osteoprotegerin, receptor activator of NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J Bone Miner Res 16(6):1004-14.
Kotterman MA, Schaffer DV. 2014. Engineering adeno-associated viruses for clinical gene therapy. Nat Rev Genet 15(7):445-51.
Lapidot T, Kollet O. 2002. The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune-deficient NOD/SCID and NOD/SCID/B2m(null) mice. Leukemia 16(10):1992-2003.
Lee CH, Jin MU, Jung HM, Lee JT, Kwon TG. 2015. Effect of dual treatment with SDF-1 and BMP-2 on ectopic and orthotopic bone formation. PLoS One 10(3):e0120051.
Li KC, Chang YH, Yeh CL, Hu YC. 2016. Healing of osteoporotic bone defects by baculovirus-engineered bone marrow-derived MSCs expressing MicroRNA sponges. Biomaterials 74:155-66.
Li SD, Huang L. 2006. Gene therapy progress and prospects: non-viral gene therapy by systemic delivery. Gene Ther 13(18):1313-9.
Liao YH, Chang YH, Sung LY, Li KC, Yeh CL, Yen TC, Hwang SM, Lin KJ, Hu YC. 2014. Osteogenic differentiation of adipose-derived stem cells and calvarial defect repair using baculovirus-mediated co-expression of BMP-2 and miR-148b. Biomaterials 35(18):4901-10.
Lin CY, Chang YH, Li KC, Lu CH, Sung LY, Yeh CL, Lin KJ, Huang SF, Yen TC, Hu YC. 2013. The use of ASCs engineered to express BMP2 or TGF-beta3 within scaffold constructs to promote calvarial bone repair. Biomaterials 34(37):9401-12.
Lin CY, Lin KJ, Kao CY, Chen MC, Lo WH, Yen TC, Chang YH, Hu YC. 2011. The role of adipose-derived stem cells engineered with the persistently expressing hybrid baculovirus in the healing of massive bone defects. Biomaterials 32(27):6505-14.
Lu CH, Yeh TS, Yeh CL, Fang YH, Sung LY, Lin SY, Yen TC, Chang YH, Hu YC. 2014. Regenerating cartilages by engineered ASCs: prolonged TGF-beta3/BMP-6 expression improved articular cartilage formation and restored zonal structure. Mol Ther 22(1):186-95.
Ma J, Both SK, Yang F, Cui FZ, Pan J, Meijer GJ, Jansen JA, van den Beucken JJ. 2014. Concise review: cell-based strategies in bone tissue engineering and regenerative medicine. Stem Cells Transl Med 3(1):98-107.
Marquez-Curtis LA, Janowska-Wieczorek A. 2013. Enhancing the migration ability of mesenchymal stromal cells by targeting the SDF-1/CXCR4 axis. Biomed Res Int 2013:561098.
Martino MM, Briquez PS, Maruyama K, Hubbell JA. 2015. Extracellular matrix-inspired growth factor delivery systems for bone regeneration. Adv Drug Deliv Rev.
Martino MM, Briquez PS, Ranga A, Lutolf MP, Hubbell JA. 2013. Heparin-binding domain of fibrin(ogen) binds growth factors and promotes tissue repair when incorporated within a synthetic matrix. Proc Natl Acad Sci U S A 110(12):4563-8.
Matsushita T, Chan YY, Kawanami A, Balmes G, Landreth GE, Murakami S. 2009. Extracellular signal-regulated kinase 1 (ERK1) and ERK2 play essential roles in osteoblast differentiation and in supporting osteoclastogenesis. Mol Cell Biol 29(21):5843-57.
Mizrahi O, Sheyn D, Tawackoli W, Kallai I, Oh A, Su S, Da X, Zarrini P, Cook-Wiens G, Gazit D and others. 2013. BMP-6 is more efficient in bone formation than BMP-2 when overexpressed in mesenchymal stem cells. Gene Ther 20(4):370-7.
Mizuno H, Tobita M, Uysal AC. 2012. Concise review: Adipose-derived stem cells as a novel tool for future regenerative medicine. Stem Cells 30(5):804-10.
Murakami G, Watabe T, Takaoka K, Miyazono K, Imamura T. 2003. Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads. Mol Biol Cell 14(7):2809-17.
Murphy WL, Simmons CA, Kaigler D, Mooney DJ. 2004. Bone regeneration via a mineral substrate and induced angiogenesis. J Dent Res 83(3):204-10.
Nakano M, Odaka K, Takahashi Y, Ishimura M, Saito I, Kanegae Y. 2005. Production of viral vectors using recombinase-mediated cassette exchange. Nucleic Acids Res 33(8):e76.
Nonnenmacher M, Weber T. 2012. Intracellular transport of recombinant adeno-associated virus vectors. Gene Ther 19(6):649-58.
Pang M, Woodward AW, Agarwal V, Guan X, Ha M, Ramachandran V, Chen X, Triplett BA, Stelly DM, Chen ZJ. 2009. Genome-wide analysis reveals rapid and dynamic changes in miRNA and siRNA sequence and expression during ovule and fiber development in allotetraploid cotton (Gossypium hirsutum L.). Genome Biol 10(11):R122.
Ponte AL, Marais E, Gallay N, Langonne A, Delorme B, Herault O, Charbord P, Domenech J. 2007. The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells 25(7):1737-45.
Raouf A, Seth A. 2000. Ets transcription factors and targets in osteogenesis. Oncogene 19(55):6455-63.
Ratajczak MZ, Zuba-Surma E, Kucia M, Reca R, Wojakowski W, Ratajczak J. 2006. The pleiotropic effects of the SDF-1-CXCR4 axis in organogenesis, regeneration and tumorigenesis. Leukemia 20(11):1915-24.
Rose FR, Oreffo RO. 2002. Bone tissue engineering: hope vs hype. Biochem Biophys Res Commun 292(1):1-7.
Salgado AJ, Coutinho OP, Reis RL. 2004. Bone tissue engineering: state of the art and future trends. Macromol Biosci 4(8):743-65.
Schmoekel HG, Weber FE, Schense JC, Gratz KW, Schawalder P, Hubbell JA. 2005. Bone repair with a form of BMP-2 engineered for incorporation into fibrin cell ingrowth matrices. Biotechnol Bioeng 89(3):253-62.
Sinn PL, Sauter SL, McCray PB, Jr. 2005. Gene therapy progress and prospects: development of improved lentiviral and retroviral vectors--design, biosafety, and production. Gene Ther 12(14):1089-98.
Somiari S, Glasspool-Malone J, Drabick JJ, Gilbert RA, Heller R, Jaroszeski MJ, Malone RW. 2000. Theory and in vivo application of electroporative gene delivery. Mol Ther 2(3):178-87.
Spicer PP, Kretlow JD, Young S, Jansen JA, Kasper FK, Mikos AG. 2012. Evaluation of bone regeneration using the rat critical size calvarial defect. Nat Protoc 7(10):1918-29.
Sundararaman S, Miller TJ, Pastore JM, Kiedrowski M, Aras R, Penn MS. 2011. Plasmid-based transient human stromal cell-derived factor-1 gene transfer improves cardiac function in chronic heart failure. Gene Ther 18(9):867-73.
Sung LY, Chen CL, Lin SY, Hwang SM, Lu CH, Li KC, Lan AS, Hu YC. 2013. Enhanced and prolonged baculovirus-mediated expression by incorporating recombinase system and in cis elements: a comparative study. Nucleic Acids Res 41(14):e139.
Szpalski C, Barr J, Wetterau M, Saadeh PB, Warren SM. 2010. Cranial bone defects: current and future strategies. Neurosurg Focus 29(6):E8.
Teicher BA, Fricker SP. 2010. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res 16(11):2927-31.
Thevenot PT, Nair AM, Shen J, Lotfi P, Ko CY, Tang L. 2010. The effect of incorporation of SDF-1alpha into PLGA scaffolds on stem cell recruitment and the inflammatory response. Biomaterials 31(14):3997-4008.
Thomas GM, Huganir RL. 2004. MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 5(3):173-83.
Tu Q, Pi M, Quarles LD. 2003. Calcyclin mediates serum response element (SRE) activation by an osteoblastic extracellular cation-sensing mechanism. J Bone Miner Res 18(10):1825-33.
Turan S, Galla M, Ernst E, Qiao J, Voelkel C, Schiedlmeier B, Zehe C, Bode J. 2011. Recombinase-mediated cassette exchange (RMCE): traditional concepts and current challenges. J Mol Biol 407(2):193-221.
Turan S, Zehe C, Kuehle J, Qiao J, Bode J. 2013. Recombinase-mediated cassette exchange (RMCE) - a rapidly-expanding toolbox for targeted genomic modifications. Gene 515(1):1-27.
Urist MR. 1965. Bone: formation by autoinduction. Science 150(3698):893-9.
Wang L, Park P, La Marca F, Than K, Rahman S, Lin CY. 2013a. Bone formation induced by BMP-2 in human osteosarcoma cells. Int J Oncol 43(4):1095-102.
Wang S, Balasundaram G. 2010. Potential cancer gene therapy by baculoviral transduction. Curr Gene Ther 10(3):214-25.
Wang Y, Mostafa NZ, Hsu CY, Rose L, Kucharki C, Yan J, Jiang H, Uludag H. 2013b. Modification of human BMSC with nanoparticles of polymeric biomaterials and plasmid DNA for BMP-2 secretion. J Surg Res 183(1):8-17.
Wei L, Kanbe K, Lee M, Wei X, Pei M, Sun X, Terek R, Chen Q. 2010. Stimulation of chondrocyte hypertrophy by chemokine stromal cell-derived factor 1 in the chondro-osseous junction during endochondral bone formation. Dev Biol 341(1):236-45.
Xie H, Cui Z, Wang L, Xia Z, Hu Y, Xian L, Li C, Xie L, Crane J, Wan M and others. 2014. PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis. Nat Med 20(11):1270-8.
Yan J, Zhang C, Zhao Y, Cao C, Wu K, Zhao L, Zhang Y. 2014. Non-viral oligonucleotide antimiR-138 delivery to mesenchymal stem cell sheets and the effect on osteogenesis. Biomaterials 35(27):7734-49.
Yang B, Lin X, Yang C, Tan J, Li W, Kuang H. 2015. Sambucus Williamsii Hance Promotes MC3T3-E1 Cells Proliferation and Differentiation via BMP-2/Smad/p38/JNK/Runx2 Signaling Pathway. Phytother Res 29(11):1692-9.
Yeung ML, Bennasser Y, Le SY, Jeang KT. 2005. siRNA, miRNA and HIV: promises and challenges. Cell Res 15(11-12):935-46.
Zhang W, Zhu C, Wu Y, Ye D, Wang S, Zou D, Zhang X, Kaplan DL, Jiang X. 2014. VEGF and BMP-2 promote bone regeneration by facilitating bone marrow stem cell homing and differentiation. Eur Cell Mater 27:1-11; discussion 11-2.
Zou X, Peng A, Xu L, Liu X, Lei T, Yao L, He Y, Chen S. 2013. Efficient auto-excision of a selectable marker gene from transgenic citrus by combining the Cre/loxP system and ipt selection. Plant Cell Rep 32(10):1601-13.
Zwingenberger S, Yao Z, Jacobi A, Vater C, Valladares RD, Li C, Nich C, Rao AJ, Christman JE, Antonios JK and others. 2014. Enhancement of BMP-2 induced bone regeneration by SDF-1alpha mediated stem cell recruitment. Tissue Eng Part A 20(3-4):810-8.