title: Regulation of mesenchymal stromal cells through fine tuning of canonical Wnt signaling.
abstract: Mesenchymal stromal cells (MSCs) have been extensively utilized for various cell therapeutic trials, but the signals regulating their stromal function remain largely unclear. Here, we show that canonical Wnt signals distinctively regulate MSCs in a biphasic manner depending on signal intensity, i.e., MSCs exhibit proliferation and progenitor self-renewal under low Wnt/β-catenin signaling, whereas they exhibit enhanced osteogenic differentiation with priming to osteoblast-like lineages under high Wnt/β-catenin signaling. Moreover, low or high levels of β-catenin in MSCs distinctly regulated the hematopoietic support of MSCs to promote proliferation or the undifferentiated state of hematopoietic progenitors, respectively. A gene expression study demonstrated that different intracellular levels of β-catenin in MSCs induce distinct transcriptomic changes in subsets of genes belonging to different gene function categories. Different β-catenin levels also induced differences in intracellular levels of the β-catenin co-factors, Tcf-1 and Lef-1. Moreover, nano-scale mass spectrometry of proteins that co-precipitated with β-catenin revealed distinctive spectra of proteins selectively interacting with β-catenin at specific expression levels. Together, these results show that Wnt/β-catenin signals can coax distinct transcription milieu to induce different transcription profiles in MSCs depending on the signal intensity and that fine-tuning of the canonical Wnt signaling intensity can regulate the phase-specific functionality of MSCs.
authors: Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, Republic of Korea.
authors: Jin-A
authors: JA
authors: Kim
authors: Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, Republic of Korea.
authors: Hyun-Kyung
authors: HK
authors: Choi
authors: Center for Cancer Evolution, Medical Research Center, The Catholic University of Korea, Republic of Korea.
authors: Tae-Min
authors: TM
authors: Kim
authors: Dept. of Biological Science, Dong-A University, Busan, Republic of Korea.
authors: Sun-Hee
authors: SH
authors: Leem
authors: Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, Republic of Korea. Electronic address: iho@catholic.ac.kr.
authors: Il-Hoan
authors: IH
authors: Oh
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D000066673:Cell Self Renewal; D002478:Cells, Cultured; D018920:Coculture Techniques; D020869:Gene Expression Profiling; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051176:beta Catenin