Review
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Dec 26, 2019; 11(12): 1084-1103
Published online Dec 26, 2019. doi: 10.4252/wjsc.v11.i12.1084
Small molecules for mesenchymal stem cell fate determination
Yu-Hao Cheng, Jing-Cheng Dong, Qin Bian
Yu-Hao Cheng, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
Jing-Cheng Dong, Qin Bian, Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
Author contributions: Cheng YH wrote the manuscript; Dong JC and Bian Q edited the manuscript and provided feedback.
Supported by the National Natural Science Foundation of China, No. 81573992.
Conflict-of-interest statement: The author has no conflict of interest to declare.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Qin Bian, MD, PhD, Department of Integrative Medicine, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai 200040, China. bianqin213@126.com
Telephone: 86-21-52889999
Received: March 26, 2019
Peer-review started: March 28, 2019
First decision: April 15, 2019
Revised: September 13, 2019
Accepted: October 14, 2019
Article in press: October 14, 2019
Published online: December 26, 2019
Processing time: 247 Days and 16 Hours
Abstract

Mesenchymal stem cells (MSCs) are adult stem cells harboring self-renewal and multilineage differentiation potential that are capable of differentiating into osteoblasts, adipocytes, or chondrocytes in vitro, and regulating the bone marrow microenvironment and adipose tissue remodeling in vivo. The process of fate determination is initiated by signaling molecules that drive MSCs into a specific lineage. Impairment of MSC fate determination leads to different bone and adipose tissue-related diseases, including aging, osteoporosis, and insulin resistance. Much progress has been made in recent years in discovering small molecules and their underlying mechanisms control the cell fate of MSCs both in vitro and in vivo. In this review, we summarize recent findings in applying small molecules to the trilineage commitment of MSCs, for instance, genistein, medicarpin, and icariin for the osteogenic cell fate commitment; isorhamnetin, risedronate, and arctigenin for pro-adipogenesis; and atractylenolides and dihydroartemisinin for chondrogenic fate determination. We highlight the underlying mechanisms, including direct regulation, epigenetic modification, and post-translational modification of signaling molecules in the AMPK, MAPK, Notch, PI3K/AKT, Hedgehog signaling pathways etc. and discuss the small molecules that are currently being studied in clinical trials. The target-based manipulation of lineage-specific commitment by small molecules offers substantial insights into bone marrow microenvironment regulation, adipose tissue homeostasis, and therapeutic strategies for MSC-related diseases.

Keywords: Mesenchymal stem cell; Mesenchymal stromal cell; Cell fate determination; Small molecules; Natural compounds; Signaling pathways

Core tip: Mesenchymal stem cells (MSCs), also called MSCs, are adult stem cells with multilineage differentiation potential. They serve crucial physiological roles, regulating the bone marrow microenvironment and adipose tissue remodeling in vivo. A complex regulatory network and signaling pathways are involved in governing MSC fate commitment. Much progress has been made in recent years in discovering small molecules and their underlying mechanisms that control the cell fate of MSCs. In this review, we summarize recent findings in applying small molecules to the trilineage cell fate commitment of MSCs, highlighting the underlying mechanisms and the current clinical trials. The small molecules for MSC fate determination offer substantial insights into bone marrow and adipose tissue homeostasis and therapeutic strategies for MSC-related diseases.