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J Cell Biochem. 2018 Nov;119(11):8872-8886. doi: 10.1002/jcb.27140. Epub 2018 Aug 4.

Reversibly immortalized human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are responsive to BMP9-induced osteogenic and adipogenic differentiation.

Shu Y1,2,3,4, Yang C1,2,3, Ji X1,2,3, Zhang L1,2,3, Bi Y1,2,3, Yang K1,2,3,5, Gong M1,2, Liu X1,2,3, Guo Q6, Su Y1,2,3, Qu X1,2,3, Nan G1,2,3, Zhao C3,4, Zeng Z3,4, Yu X3,4, Zhang R3,4, Yan S3,4, Lei J3,4, Wu K3,4, Wu Y3,7, An L3,8, Huang S3,4, Gong C3,9, Yuan C3,10, Liu W3,4, Huang B3,4, Feng Y3,4, Zhang B3,8, Dai Z3,11, Shen Y3,12, Luo W3,4, Wang X3,4, Haydon RC3, Luu HH3, Reid RR3,13, Wolf JM3, Lee MJ3, He TC1,2,3,4, Li Y1,2,3.

Author information

1
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.
2
Departments of Pediatric Surgery, Cardiology, and Orthopaedic Surgery, The Children's Hospital of Chongqing Medical University, Chongqing, China.
3
Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois.
4
Ministry of Education Key Laboratory of Diagnostic Medicine, the School of Laboratory Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China.
5
Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing, China.
6
Chongqing Quality Testing and Inspection Center for Medical Devices, Chongqing, China.
7
Department of Immunology and Microbiology, Beijing University of Chinese Medicine, Beijing, China.
8
Key Laboratory of Orthopaedic Surgery of Gansu Province, Department of Orthopaedic Surgery, The Second Hospital of Lanzhou University, Lanzhou, China.
9
Department of Surgery, The Affiliated Zhongnan Hospital of Wuhan University, Wuhan, China.
10
Department of Biochemistry and Molecular Biology, China Three Gorges University School of Medicine, Yichang, China.
11
Department of Orthopaedic Surgery, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China.
12
Department of Orthopaedic Surgery, Xiangya Second Hospital of Central South University, Changsha, China.
13
Laboratory of Craniofacial Biology and Development, Section of Plastic Surgery, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois.

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.

KEYWORDS:

BMP9-induced osteogenic differentiation; SV40 T antigen immortalization; immunotherapy; mesenchymal stem cells (MSCs); regenerative medicine; umbilical cord-derived MSCs (UC-MSCs)

PMID:
30076626
PMCID:
PMC6195452
[Available on 2019-11-01]
DOI:
10.1002/jcb.27140

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