Theranostics 2019; 9(1):290-310. doi:10.7150/thno.28671

Research Paper

Direct in vivo application of induced pluripotent stem cells is feasible and can be safe

Meng Xiang1*, Meng Lu1*, Jing Quan1*, Ming Xu1*, Dan Meng1, Anfeng Cui1, Ning Li1, Yingying Liu1, Peng Lu1, Xueling Kang1, Xiaokai Wang1, Ning Sun1, Meng Zhao1, Qiujuan Liang1, Lili Le1, Xinhong Wang1, Jianyi Zhang2, Sifeng Chen1✉

1. Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, P.R. China
2. Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, USA
*These authors contributed equally.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
Xiang M, Lu M, Quan J, Xu M, Meng D, Cui A, Li N, Liu Y, Lu P, Kang X, Wang X, Sun N, Zhao M, Liang Q, Le L, Wang X, Zhang J, Chen S. Direct in vivo application of induced pluripotent stem cells is feasible and can be safe. Theranostics 2019; 9(1):290-310. doi:10.7150/thno.28671. Available from

File import instruction


Increasing evidence suggests the consensus that direct in vivo application of induced pluripotent stem cells (iPSCs) is infeasible may not be true.

Methods: Teratoma formation and fate were examined in 53 normal and disease conditions involving brain, lung, liver, kidney, islet, skin, hind limb, and arteries.

Results: Using classic teratoma generation assays, which require iPSCs to be congregated and confined, all mouse, human, and individualized autologous monkey iPSCs tested formed teratoma, while iPSC-derived cells did not. Intravenously or topically-disseminated iPSCs did not form teratomas with doses up to 2.5×108 iPSCs/kg and observation times up to 18 months, regardless of host tissue type; autologous, syngeneic, or immune-deficient host animals; presence or absence of disease; disease type; iPSC induction method; commercial or self-induced iPSCs; mouse, human, or monkey iPSCs; frequency of delivery; and sex. Matrigel-confined, but not PBS-suspended, syngeneic iPSCs delivered into the peritoneal cavity or renal capsule formed teratomas. Intravenously administered iPSCs were therapeutic with a dose as low as 5×106/kg and some iPSCs differentiated into somatic cells in injured organs. Disseminated iPSCs trafficked into injured tissue and survived significantly longer in injured than uninjured organs. In disease-free animals, no intravenously administered cell differentiated into an unwanted long-lasting cell or survived as a quiescent stem cell. In coculture, the stem cell medium and dominant cell-type status were critical for iPSCs to form cell masses.

Conclusion: Teratoma can be easily and completely avoided by disseminating the cells. Direct in vivo iPSC application is feasible and can be safe.

Keywords: induced pluripotent stem cells, teratoma, cellular microenvironment, monkey