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.

Heterogeneous Niche Activity of Ex-Vivo Expanded MSCs as Factor for Variable Outcomes in Hematopoietic Recovery

“…Similarly, we recently showed that fine tuning the mesenchymal niche is critical for regulating the regenerative activity of HSCs [19] and that functional alterations of MSCs are related to heterogeneous clinical prognosis in hematological malignancies[20]. The niche activity of MSCs can thus exert a significant impact on the regenerative activity of HSCs.…”

Transdifferentiation of adipocytes to osteoblasts: potential for orthopaedic treatment

“…[78] Adipo-to-osteo transdifferentiation Wnt/b-catenin signalling is a master regulator of adipocyte and osteoblast maturation whereby an accumulation of bcatenin was observed to cause a dose-dependent increase in osteogenesis and a dose-dependent decrease in adipocyte differentiation. [79,80] For instance, b-catenin knockout within the preosteoblasts of mice resulted in an increase in bone marrow adiposity and a decreased bone mass. [83] Wnt-3a is documented to be an inducer of Wnt signalling so that culturing mouse BMSC-derived preadipocyte and preosteoblast cells in a Wnt-3a conditioned medium led to the induction of the Wnt pathway and upregulation of the TCF/LEF gene within preosteoblasts.…”

“…[83] In addition, MSCs demonstrating b-catenin expression were associated with bone mineralisation, an upregulated ALP expression and a downregulation of aP2 and PPARc expression. [79] Furthermore, b-catenin acts as a transactivation molecule depending on the levels accumulated within MSCs. [79] Low b-catenin levels result in the expression of genes responsible for cell cycle regulation whilst high b-catenin levels are associated with the expression of genes responsible for pathway signalling like that in osteoblast maturation.…”

“…[79] Furthermore, b-catenin acts as a transactivation molecule depending on the levels accumulated within MSCs. [79] Low b-catenin levels result in the expression of genes responsible for cell cycle regulation whilst high b-catenin levels are associated with the expression of genes responsible for pathway signalling like that in osteoblast maturation. [79] In contrast, the non-canonical Wnt-5a has been observed to activate Runx2 expression and suppresses the activity of PPARc via histone methyltransferase-induced chromatin inactivation.…”

“…[79] Low b-catenin levels result in the expression of genes responsible for cell cycle regulation whilst high b-catenin levels are associated with the expression of genes responsible for pathway signalling like that in osteoblast maturation. [79] In contrast, the non-canonical Wnt-5a has been observed to activate Runx2 expression and suppresses the activity of PPARc via histone methyltransferase-induced chromatin inactivation. [86] In other words, this non-canonical pathway has been implicated to contribute to osteoblastogenesis from MSCs.…”