Lithium stimulates human bone marrow derived mesenchymal stem cell proliferation through GSK‐3β‐dependent β‐catenin/Wnt pathway activation

Abstract

Mesenchymal stem cells (MSCs) are multipotent cells that have been widely used in cell based transplantation therapy. The use of MSCs requires in vitro expansion in order to fulfill their regenerative capacity. Therefore the proliferative ability of MSCs is one of the key factors which determine MSC therapeutic efficacy. In the present study, we showed for the first time that lithium, a well-known antidepressant, reversibly promoted the proliferation of human bone marrow derived MSCs in vitro. MSCs treated with 5 mM lithium proliferated more rapidly than untreated cells without undergoing apoptosis. Lithium increased the proportion of cells in S phase as well as cyclin D1 expression. Mechanistic studies revealed that these effects were dependent upon the activation of the glycogen synthase kinase 3b (GSK-3b) mediated canonical Wnt pathway. Lithium induced Ser9 phosphorylation, which results in the inhibition of GSK-3b activity, b-catenin accumulation and Wnt pathway activation. Utilizing a specific GSK-3b inhibitor SB216763 or siRNA-mediated inhibition of GSK-3b produced effects similar to those induced by lithium. In contrast, either quercetin, an inhibitor of the b-catenin/TCF pathway, or siRNA-mediated knockdown of b-catenin abolished the proliferative effect of lithium, suggesting that lithium stimulates MSC proliferation via the GSK-3b-dependent b-catenin/ Wnt pathway. Collectively, these studies elucidate a novel role of lithium, which may not only provide a simple and effective way to strengthen MSC transplantation therapy efficacy but also shed light on lithium's clinical application for the treatment of certain disorders resulting from b-catenin/ Wnt pathway suppression.

Enhanced Chondrogenic Differentiation of Human Umbilical Cord Wharton's Jelly Derived Mesenchymal Stem Cells by GSK-3 Inhibitors

“…β-catenin accumulation activates transcription in conjunction with co-transcription factors, LEFs/TCFs [32]. It was previously reported that LiCl (5–10 mM) can effectively induce the canonical Wnt signaling pathway and mediate cell differentiation of MSCs [16,17,33] and articular chondrocytes [34]. SB216763 has been shown to regulate cell proliferation and survival and to induce the transcription of β-catenin-dependent genes [24].…”

Wnt/β-catenin signaling regulates Dental Pulp Stem Cells’ responses to pulp injury by resinous monomers

“…Han et al [39] showed increase of cell proliferation of human periodontal ligament stem cells (hPDLSCs) up to 5 mM and a decrease at 10 and 20 mM. Zhu et al [40] showed that lithium stimulated proliferation of MSCs up to 5 mM and inhibited at higher concentrations, being able to induce apoptosis above 10 mM. Cell cycle analysis (Fig.…”

Lithium Reversibly Inhibits Schwann Cell Proliferation and Differentiation Without Inducing Myelin Loss

“…In normal cells, on the contrary, both the action of lithium and that of GSK-3β inhibitors has been prevalently linked to an increase rather than a decrease in cell proliferation rates. Examples are neural precursor and mesenchymal stem cells that respond to lithium treatment by undergoing proliferation, typically in a GSK-3β/β-catenin-dependent manner [2,3]. Whether lithium compounds differentially affect the proliferation of normal and cancer SCs remains an open but intriguing question.…”

“…Lithium is a well-recognized direct inhibitor of the kinase activity of glycogen synthase kinase (GSK)-3β [1], which is a downstream effector within the signaling network driven by phosphatidylinositol-3-kinase (PI3-K) and protein kinase B or Akt. The interaction of lithium with these ubiquitous pathways has provided a molecular basis for its widespread role in stem cell lineage specification [2], proliferation [3] and differentiation in a variety of cell types [4,5]. …”