CoCl₂, a mimic of hypoxia, enhances bone marrow mesenchymal stem cells migration and osteogenic differentiation via STAT3 signaling pathway

Abstract

Mesenchymal stem cells homing and migration is a crucial step during bone fracture healing. Hypoxic environment in fracture site induces bone marrow mesenchymal stem cells (BMSCs) migration, but its mechanism remains unclear. Our previous study and studies by other groups have reported the involvement of signal transducer and activator of transcription 3 (STAT3) pathway in cell migration. However, the role of STAT3 pathway in hypoxia-induced cell migration is still unknown. In this study, we investigated the role of STAT3 signaling in hypoxia-induced BMSCs migration and osteogenic differentiation. BMSCs isolated from C57BL/6 male mice were cultured in the presence of cobalt chloride (CoCl ) to simulate intracellular hypoxia. Hypoxia enhanced BMSCs migration, and upregulated cell migration related gene expression, that is, metalloproteinase (MMP) 7, MMP9, and C-X-C motif chemokine receptor 4. Hypoxia enhanced the phosphorylation of STAT3, and cell migration related proteins: c-jun n-terminal kinase (JNK), focal of adhesion kinase (FAK), extracellular regulated protein kinases, and protein kinase B 1/2 (ERK1/2). Moreover, hypoxia enhanced expression of osteogenic differentiation marker. Inhibition of STAT3 suppressed the hypoxia-induced BMSCs migration, cell migration related signaling molecules phosphorylation, and osteogenic differentiation related gene expression. In conclusion, our result indicates that hypoxia-induced BMSCs migration and osteogenic differentiation is via STAT3 phosphorylation and involves the cooperative activity of the JNK, FAK, and MMP9 signaling pathways.

Chronic Hypoxia-Induced Microvessel Proliferation and Basal Membrane Degradation in the Bone Marrow of Rats Regulated through the IL-6/JAK2/STAT3/MMP-9 Pathway

“…erefore, after STAT3 inhibitor treatment, endothelial cell lineages and their common progenitor cells were inhibited resulting in suppression of microvessel proliferation. It has been shown that the BMSCs in the bone marrow were inhibited by the inhibition of JAK2/STAT3 signaling which is consistent with our results [59]. Additionally, our results showed that, under hypoxic condition, the microvessels from the vascular endothelial cells were enhanced by STAT3 overexpression.…”

“…On the one hand, previous studies showed that hematopoietic and endothelial cell lineages share common progenitors that affect the proliferation and differentiation of bone marrow-derived or umbilical cord blood-derived endothelial progenitor cells, which in turn promote angiogenesis [56,57]. On the other hand, it is well known that the bone marrow is characterized by the cellular diversity and complex functions [58].Importantly, vascular endothelial cells play a critical role in microvessels of the bone marrow [59,60]. Some studies showed that STAT3 is expressed in vascular endothelial cells [19].…”

HIF-stabilization prevents delayed fracture healing

“…Interestingly, Cobalt(II) chloride, another HIF-stabilizer also increased osteogenic differentiation as recently reported (73). Nevertheless, the counteracting potential of DFO for GC-induced inhibition of osteogenic differentiation as shown in the present study, has not been reported, yet.…”

Effects of cobalt chloride on the stem cell marker expression and osteogenic differentiation of stem cells from human exfoliated deciduous teeth

“…This result corresponds with previous studies that reported the inhibitory effect of CoCl 2 on osteogenic differentiation in hDPCs (Laksana et al 2017) and hPDLCs (Osathanon et al 2015). However, it was found that CoCl 2 upregulated osteogenic gene expression in BMSCs (Yu et al 2018). Differences in cell types may contribute to such disparities.…”