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Reversibly immortalized human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are responsive to BMP9-induced osteogenic and adipogenic differentiation.
J Cell Biochem 2018; 119(11):8872-8886JC

Abstract

Human mesenchymal stem cells (MSCs) are a heterogeneous subset of nonhematopoietic multipotent stromal stem cells and can differentiate into mesodermal lineage, such as adipocytes, osteocytes, and chondrocytes, as well as ectodermal and endodermal lineages. Human umbilical cord (UC) is one of the most promising sources of MSCs. However, the molecular and cellular characteristics of UC-derived MSCs (UC-MSCs) require extensive investigations, which are hampered by the limited lifespan and the diminished potency over passages. Here, we used the piggyBac transposon-based simian virus 40 T antigen (SV40T) immortalization system and effectively immortalized UC-MSCs, yielding the iUC-MSCs. A vast majority of the immortalized lines are positive for MSC markers but not for hematopoietic markers. The immortalization phenotype of the iUC-MSCs can be effectively reversed by flippase recombinase-induced the removal of SV40T antigen. While possessing long-term proliferation capability, the iUC-MSCs are not tumorigenic in vivo. Upon bone morphogenetic protein 9 (BMP9) stimulation, the iUC-MSC cells effectively differentiate into osteogenic, chondrogenic, and adipogenic lineages both in vitro and in vivo, which is indistinguishable from that of primary UC-MSCs, indicating that the immortalized UC-MSCs possess the characteristics similar to that of their primary counterparts and retain trilineage differentiation potential upon BMP9 stimulation. Therefore, the engineered iUC-MSCs should be a valuable alternative cell source for studying UC-MSC biology and their potential utilities in immunotherapies and regenerative medicine.

Authors+Show Affiliations

Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital, Chongqing Medical University, Chongqing, China. Departments of Pediatric Surgery, Cardiology, and Orthopaedic Surgery, The Children's Hospital of Chongqing Medical University, Chongqing, China. Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Ministry of Education Key Laboratory of Diagnostic Medicine, the School of Laboratory Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital, Chongqing Medical University, Chongqing, China. Departments of Pediatric Surgery, Cardiology, and Orthopaedic Surgery, The Children's Hospital of Chongqing Medical University, Chongqing, China. Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois.Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital, Chongqing Medical University, Chongqing, China. Departments of Pediatric Surgery, Cardiology, and Orthopaedic Surgery, The Children's Hospital of Chongqing Medical University, Chongqing, China. Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois.Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital, Chongqing Medical University, Chongqing, China. Departments of Pediatric Surgery, Cardiology, and Orthopaedic Surgery, The Children's Hospital of Chongqing Medical University, Chongqing, China. Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois.Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital, Chongqing Medical University, Chongqing, China. Departments of Pediatric Surgery, Cardiology, and Orthopaedic Surgery, The Children's Hospital of Chongqing Medical University, Chongqing, China. Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois.Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital, Chongqing Medical University, Chongqing, China. Departments of Pediatric Surgery, Cardiology, and Orthopaedic Surgery, The Children's Hospital of Chongqing Medical University, Chongqing, China. Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing, China.Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital, Chongqing Medical University, Chongqing, China. Departments of Pediatric Surgery, Cardiology, and Orthopaedic Surgery, The Children's Hospital of Chongqing Medical University, Chongqing, China.Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital, Chongqing Medical University, Chongqing, China. Departments of Pediatric Surgery, Cardiology, and Orthopaedic Surgery, The Children's Hospital of Chongqing Medical University, Chongqing, China. Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois.Chongqing Quality Testing and Inspection Center for Medical Devices, Chongqing, China.Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital, Chongqing Medical University, Chongqing, China. Departments of Pediatric Surgery, Cardiology, and Orthopaedic Surgery, The Children's Hospital of Chongqing Medical University, Chongqing, China. Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois.Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital, Chongqing Medical University, Chongqing, China. Departments of Pediatric Surgery, Cardiology, and Orthopaedic Surgery, The Children's Hospital of Chongqing Medical University, Chongqing, China. Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois.Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital, Chongqing Medical University, Chongqing, China. Departments of Pediatric Surgery, Cardiology, and Orthopaedic Surgery, The Children's Hospital of Chongqing Medical University, Chongqing, China. Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Ministry of Education Key Laboratory of Diagnostic Medicine, the School of Laboratory Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Ministry of Education Key Laboratory of Diagnostic Medicine, the School of Laboratory Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Ministry of Education Key Laboratory of Diagnostic Medicine, the School of Laboratory Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Ministry of Education Key Laboratory of Diagnostic Medicine, the School of Laboratory Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Ministry of Education Key Laboratory of Diagnostic Medicine, the School of Laboratory Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Ministry of Education Key Laboratory of Diagnostic Medicine, the School of Laboratory Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Ministry of Education Key Laboratory of Diagnostic Medicine, the School of Laboratory Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Department of Immunology and Microbiology, Beijing University of Chinese Medicine, Beijing, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Key Laboratory of Orthopaedic Surgery of Gansu Province, Department of Orthopaedic Surgery, The Second Hospital of Lanzhou University, Lanzhou, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Ministry of Education Key Laboratory of Diagnostic Medicine, the School of Laboratory Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Department of Surgery, The Affiliated Zhongnan Hospital of Wuhan University, Wuhan, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Department of Biochemistry and Molecular Biology, China Three Gorges University School of Medicine, Yichang, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Ministry of Education Key Laboratory of Diagnostic Medicine, the School of Laboratory Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Ministry of Education Key Laboratory of Diagnostic Medicine, the School of Laboratory Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Ministry of Education Key Laboratory of Diagnostic Medicine, the School of Laboratory Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Key Laboratory of Orthopaedic Surgery of Gansu Province, Department of Orthopaedic Surgery, The Second Hospital of Lanzhou University, Lanzhou, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Department of Orthopaedic Surgery, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Department of Orthopaedic Surgery, Xiangya Second Hospital of Central South University, Changsha, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Ministry of Education Key Laboratory of Diagnostic Medicine, the School of Laboratory Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Ministry of Education Key Laboratory of Diagnostic Medicine, the School of Laboratory Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Laboratory of Craniofacial Biology and Development, Section of Plastic Surgery, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois.Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois.Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital, Chongqing Medical University, Chongqing, China. Departments of Pediatric Surgery, Cardiology, and Orthopaedic Surgery, The Children's Hospital of Chongqing Medical University, Chongqing, China. Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois. Ministry of Education Key Laboratory of Diagnostic Medicine, the School of Laboratory Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.Stem Cell Biology and Therapy Laboratory, Ministry of Education Key Laboratory of Child Development and Disorders, The Children's Hospital, Chongqing Medical University, Chongqing, China. Departments of Pediatric Surgery, Cardiology, and Orthopaedic Surgery, The Children's Hospital of Chongqing Medical University, Chongqing, China. Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

30076626

Citation

Shu, Yi, et al. "Reversibly Immortalized Human Umbilical Cord-derived Mesenchymal Stem Cells (UC-MSCs) Are Responsive to BMP9-induced Osteogenic and Adipogenic Differentiation." Journal of Cellular Biochemistry, vol. 119, no. 11, 2018, pp. 8872-8886.
Shu Y, Yang C, Ji X, et al. Reversibly immortalized human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are responsive to BMP9-induced osteogenic and adipogenic differentiation. J Cell Biochem. 2018;119(11):8872-8886.
Shu, Y., Yang, C., Ji, X., Zhang, L., Bi, Y., Yang, K., ... Li, Y. (2018). Reversibly immortalized human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are responsive to BMP9-induced osteogenic and adipogenic differentiation. Journal of Cellular Biochemistry, 119(11), pp. 8872-8886. doi:10.1002/jcb.27140.
Shu Y, et al. Reversibly Immortalized Human Umbilical Cord-derived Mesenchymal Stem Cells (UC-MSCs) Are Responsive to BMP9-induced Osteogenic and Adipogenic Differentiation. J Cell Biochem. 2018;119(11):8872-8886. PubMed PMID: 30076626.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reversibly immortalized human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are responsive to BMP9-induced osteogenic and adipogenic differentiation. AU - Shu,Yi, AU - Yang,Chao, AU - Ji,Xiaojuan, AU - Zhang,Linghuan, AU - Bi,Yang, AU - Yang,Ke, AU - Gong,Mengjia, AU - Liu,Xing, AU - Guo,Qi, AU - Su,Yuxi, AU - Qu,Xiangyang, AU - Nan,Guoxin, AU - Zhao,Chen, AU - Zeng,Zongyue, AU - Yu,Xinyi, AU - Zhang,Ruyi, AU - Yan,Shujuan, AU - Lei,Jiayan, AU - Wu,Ke, AU - Wu,Ying, AU - An,Liping, AU - Huang,Shifeng, AU - Gong,Cheng, AU - Yuan,Chengfu, AU - Liu,Wei, AU - Huang,Bo, AU - Feng,Yixiao, AU - Zhang,Bo, AU - Dai,Zhengyu, AU - Shen,Yi, AU - Luo,Wenping, AU - Wang,Xi, AU - Haydon,Rex C, AU - Luu,Hue H, AU - Reid,Russell R, AU - Wolf,Jennifer Moriatis, AU - Lee,Michael J, AU - He,Tong-Chuan, AU - Li,Yasha, Y1 - 2018/08/04/ PY - 2018/02/07/received PY - 2018/05/14/accepted PY - 2018/8/5/pubmed PY - 2018/8/5/medline PY - 2018/8/5/entrez KW - BMP9-induced osteogenic differentiation KW - SV40 T antigen immortalization KW - immunotherapy KW - mesenchymal stem cells (MSCs) KW - regenerative medicine KW - umbilical cord-derived MSCs (UC-MSCs) SP - 8872 EP - 8886 JF - Journal of cellular biochemistry JO - J. Cell. Biochem. VL - 119 IS - 11 N2 - Human mesenchymal stem cells (MSCs) are a heterogeneous subset of nonhematopoietic multipotent stromal stem cells and can differentiate into mesodermal lineage, such as adipocytes, osteocytes, and chondrocytes, as well as ectodermal and endodermal lineages. Human umbilical cord (UC) is one of the most promising sources of MSCs. However, the molecular and cellular characteristics of UC-derived MSCs (UC-MSCs) require extensive investigations, which are hampered by the limited lifespan and the diminished potency over passages. Here, we used the piggyBac transposon-based simian virus 40 T antigen (SV40T) immortalization system and effectively immortalized UC-MSCs, yielding the iUC-MSCs. A vast majority of the immortalized lines are positive for MSC markers but not for hematopoietic markers. The immortalization phenotype of the iUC-MSCs can be effectively reversed by flippase recombinase-induced the removal of SV40T antigen. While possessing long-term proliferation capability, the iUC-MSCs are not tumorigenic in vivo. Upon bone morphogenetic protein 9 (BMP9) stimulation, the iUC-MSC cells effectively differentiate into osteogenic, chondrogenic, and adipogenic lineages both in vitro and in vivo, which is indistinguishable from that of primary UC-MSCs, indicating that the immortalized UC-MSCs possess the characteristics similar to that of their primary counterparts and retain trilineage differentiation potential upon BMP9 stimulation. Therefore, the engineered iUC-MSCs should be a valuable alternative cell source for studying UC-MSC biology and their potential utilities in immunotherapies and regenerative medicine. SN - 1097-4644 UR - https://www.unboundmedicine.com/medline/citation/30076626/Reversibly_immortalized_human_umbilical_cord_derived_mesenchymal_stem_cells__UC_MSCs__are_responsive_to_BMP9_induced_osteogenic_and_adipogenic_differentiation_ L2 - https://doi.org/10.1002/jcb.27140 DB - PRIME DP - Unbound Medicine ER -