PSA-NCAM-negative neural crest cells emerging during neural induction of pluripotent stem cells cause mesodermal tumors and unwanted grafts.
Tumorigenic potential of human pluripotent stem cells (hPSCs) is an important issue in clinical applications. Despite many efforts, PSC-derived neural precursor cells (NPCs) have repeatedly induced tumors in animal models even though pluripotent cells were not detected. We found that polysialic acid-neural cell adhesion molecule (PSA-NCAM)(-) cells among the early NPCs caused tumors, whereas PSA-NCAM(+) cells were nontumorigenic. Molecular profiling, global gene analysis, and multilineage differentiation of PSA-NCAM(-) cells confirm that they are multipotent neural crest stem cells (NCSCs) that could differentiate into both ectodermal and mesodermal lineages. Transplantation of PSA-NCAM(-) cells in a gradient manner mixed with PSA-NCAM(+) cells proportionally increased mesodermal tumor formation and unwanted grafts such as PERIPHERIN(+) cells or pigmented cells in the rat brain. Therefore, we suggest that NCSCs are a critical target for tumor prevention in hPSC-derived NPCs, and removal of PSA-NCAM(-) cells eliminates the tumorigenic potential originating from NCSCs after transplantation.
Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea.
Dongjin R
DR
Lee
Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea.
Jeong-Eun
JE
Yoo
Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea.
Jae Souk
JS
Lee
Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea.
Sanghyun
S
Park
Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea.
Junwon
J
Lee
Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea.
Chul-Yong
CY
Park
Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea.
Eunhyun
E
Ji
Cell Therapy Center and Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea.
Han-Soo
HS
Kim
Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Gyeonggi-do 463-840, Korea.
Dong-Youn
DY
Hwang
Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Korea. Electronic address: sonnet10@korea.ac.kr.
Dae-Sung
DS
Kim
Department of Physiology and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Korea. Electronic address: dwkim2@yuhs.ac.
Dong-Wook
DW
Kim
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D004475:Ectoderm / Q000166:cytology / Q000378:metabolism; D000066449:Human Embryonic Stem Cells / Q000166:cytology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D009369:Neoplasms / Q000209:etiology / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism*; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D064531:Peripherins / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012794:Sialic Acids / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
D039842:Neural Cell Adhesion Molecule L1; D064531:Peripherins; D012794:Sialic Acids; C103469:polysialyl neural cell adhesion molecule