title: Electrospun scaffolds for multiple tissues regeneration in vivo through topography dependent induction of lineage specific differentiation.
abstract: Physical topographic cues from various substrata have been shown to exert profound effects on the growth and differentiation of stem cells due to their niche-mimicking features. However, the biological function of different topographic materials utilized as bio-scaffolds in vivo have not been rigorously characterized. This study investigated the divergent differentiation pathways of mesenchymal stem cells (MSCs) and neo-tissue formation trigged by aligned and randomly-oriented fibrous scaffolds, both in vitro and in vivo. The aligned group was observed to form more mature tendon-like tissue in the Achilles tendon injury model, as evidenced by histological scoring and collagen I immunohistochemical staining data. In contrast, the randomly-oriented group exhibited much chondrogenesis and subsequent bone tissue formation through ossification. Additionally, X-ray imaging and osteocalcin immunohistochemical staining also demonstrated that osteogenesis in vivo is driven by randomly oriented topography. Furthermore, MSCs on the aligned substrate exhibited tenocyte-like morphology and enhanced tenogenic differentiation compared to cells grown on randomly-oriented scaffold. qRT-PCR analysis of osteogenic marker genes and alkaline phosphatase (ALP) staining demonstrated that MSCs cultured on randomly-oriented fiber scaffolds displayed enhanced osteogenic differentiation compared with cells cultured on aligned fiber scaffolds. Finally, it was demonstrated that cytoskeletal tension release abrogated the divergent differentiation pathways on different substrate topography. Collectively, these findings illustrate the relationship between topographic cues of the scaffold and their inductive role in tissue regeneration; thus providing an insight into future development of smart functionalized bio-scaffold design and its application in tissue engineering.
authors.affiliation: Department of Sports Medicine, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Zi
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Department of Sports Medicine, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Rehabilitation, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Hai-Xin
authors.initials: HX
authors.lastname: Song
authors.affiliation: Department of Sports Medicine, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Jia-Jie
authors.initials: JJ
authors.lastname: Hu
authors.affiliation: Department of Sports Medicine, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Qiao-Mei
authors.initials: QM
authors.lastname: Tang
authors.affiliation: Department of Sports Medicine, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Department of Orthopedic Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Wei-Liang
authors.initials: WL
authors.lastname: Shen
authors.affiliation: Department of Sports Medicine, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Jia-Lin
authors.initials: JL
authors.lastname: Chen
authors.affiliation: Department of Sports Medicine, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Biosystems Science & Engineering (D-BSSE), ETH-Zurich, Basel, Switzerland.
authors.forename: Boon Chin
authors.initials: BC
authors.lastname: Heng
authors.affiliation: Department of Sports Medicine, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, China; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Electronic address: hwoy@zju.edu.cn.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Ouyang
mesh_terms: D000125:Achilles Tendon / Q000000981:diagnostic imaging / Q000502:physiology; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001696:Biomechanical Phenomena; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D019344:Lactic Acid / Q000737:chemistry; D059630:Mesenchymal Stem Cells; D051379:Mice; D057139:Nanofibers / Q000737:chemistry / Q000648:ultrastructure; D010012:Osteogenesis; D011091:Polyesters; D011108:Polymers / Q000737:chemistry; D011859:Radiography; D051381:Rats; D012038:Regeneration / Q000502:physiology*; D013194:Staining and Labeling; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds / Q000737:chemistry*; D014945:Wound Healing; D014965:X-Rays
chemical_list: D015415:Biomarkers; D011091:Polyesters; D011108:Polymers; D019344:Lactic Acid; C033616:poly(lactide); D000469:Alkaline Phosphatase
keywords: Bio-scaffold topography; Bone formation; Mesenchymal stem cells; Tendon regeneration; Tissue engineering