iPSC-Derived MSCs Are Shown to Accelerate Healing in IBD Cases
This paper shows that human induced pluripotent stem cell (iPSC)-derived MSCs may be helpful in treating inflammatory bowel disease (IBD).
ABSTRACT
Human induced pluripotent stem cell-derived mesenchymal stem cells promote healing via TNF-α-stimulated gene-6 in inflammatory bowel disease models.
Cell Death Dis. 2019 Sep 26;10(10):718. doi: 10.1038/s41419-019-1957-7.
Yang H1,2, Feng R1, Fu Q3, Xu S1, Hao X1, Qiu Y1, Feng T1, Zeng Z1, Chen M4, Zhang S5.
Author information
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. [email protected].
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. [email protected].
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. [email protected].
Abstract
Therapeutic applications of tissue-derived mesenchymal stem cells (MSCs) are hindered by their limited expansion ability and variation across donors. Human induced pluripotent stem cell (iPSC)-derived MSCs show greater expandability and therefore offer potential for use in tissue repair therapies. Here we explored the regenerative effects of iPSC-MSCs and the mechanisms by which iPSC-MSCs promote mucosal healing via tumor necrosis factor-α-stimulated gene 6 (TSG-6) in mouse models of inflammatory bowel disease (IBD). Human iPSCs were induced to differentiate into MSCs following a clinically compliant protocol. The iPSC-MSC treatment promoted mucosal healing in colitic mice, accompanied by increased epithelial cell proliferation, CD44-positive cells, and Lgr5-positive cells. TSG-6 knockdown in iPSC-MSCs or blocking of hyaluronan-CD44 interactions by PEP-1 abrogated the therapeutic effects of iPSC-MSCs, whereas use of recombinant TSG-6 showed therapeutic effects similar to those of iPSC-MSCs. A mouse or patient-derived organoid culture system was developed. Organoids co-cultured with iPSC-MSCs showed increased epithelial cell proliferation, CD44-positive cells, and Lgr5-positive cells, which was abolished by TSG-6 knockdown. TSG-6-induced promoting effects in organoids were dependent on Akt activation and abrogated by the anti-CD44 antibody or MK2206. In conclusion, iPSC-MSCs promoted epithelial cell proliferation to accelerate mucosal healing in a murine colitis model via TSG-6 through hyaluronan-CD44 interactions in an Akt-dependent manner, demonstrating a patient-specific “off-the-shelf” format for IBD treatment.
PMID:31558705
PMCID:PMC6763610
DOI:10.1038/s41419-019-1957-7