Sonic hedgehog (SHH) signaling improves the angiogenic potential of Wharton’s jelly-derived mesenchymal stem cells (WJ-MSC)

Abstract

BackgroundWharton’s jelly-derived mesenchymal stem cells (WJ-MSC) show remarkable therapeutic potential to repair tissue upon injury via paracrine signaling by secreting diverse trophic factors that promote angiogenesis. However, the mechanisms and signaling pathways that regulate the induction of these specific factors are still mostly unknown. Emerging evidence suggests that Sonic hedgehog (SHH) plays a central role in angiogenesis and tissue maintenance. However, its contribution to the angiogenic potential of MSC has not been fully addressed. The aim of this work was to characterize the expression of the SHH pathway components in WJ-MSC primary cultures and to evaluate their angiogenic responsiveness to SHH signaling.MethodsPrimary cell cultures obtained from human umbilical cords were treated with pharmacological modulators of the SHH pathway. We evaluated the modulation of diverse trophic factors in cell lysates, conditioned medium, and functional in vitro assays. In addition, we determined the angiogenic potential of the SHH pathway in the chicken chorioallantoic membrane, an in vivo model.ResultsOur results show that WJ-MSC express components of the canonical SHH pathway and are activated by its signaling. In fact, we provide evidence of basal autocrine/paracrine SHH signaling in WJ-MSC. SHH pathway stimulation promotes the secretion of angiogenic factors such as activin A, angiogenin, angiopoietin 1, granulocyte-macrophage colony-stimulating factor, matrix metallometallopeptidase -9, and urokinase-type plasminogen activator, enhancing the pro-angiogenic capabilities of WJ-MSC both in vitro and in vivo.ConclusionWJ-MSC are a cell population responsive to SHH pathway stimulation. Basal SHH signaling is in part responsible for the angiogenic inductive properties of WJ-MSC. Overall, exogenous activation of the SHH pathway enhances the angiogenic properties of WJ-MSC, making this cell population an ideal target for treating tissue injury.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0653-8) contains supplementary material, which is available to authorized users.

Cell Secretome: Basic Insights and Therapeutic Opportunities for CNS Disorders

“…Additional molecular methods have been used to modulate the secretome profile such as the pre-activation of cells with signals to stimulate the sonic hedgehog (SHH) pathway; in this case, Wharton's jelly (WJ)-derived mesenchymal stem cell secretome improved their angiogenic potential when compared with control [54]. The use of drugs, as in the case of trimetazidine and diazoxide, also seems to play a role in human embryonic-derived mesenchymal stem cell secretome when preconditioned with a drug; this primed secretome promotes the increase of immunomodulatory molecules by peripheral blood mononuclear cells (PBMCs) such as IL-10, TNF-α, and IL-1β [55].…”

Ixazomib Improves Bone Remodeling and Counteracts Sonic Hedgehog Signaling Inhibition Mediated by Myeloma Cells

“…In MM, a representative ratio between MSCs and PCs is about 1/100 000 1/1 000 000 [46,47]. This leads to a substantial deprivation of endogenous SHH stimulation on MSCs, thus, bending the differentiation of MSCs and reducing osteoblastogenesis [48,49]. As such, several groups have suggested stromal-derived SHH as a minor player in MM pathogenesis, even if further investigations are needed to better dissect this mechanisms [44,48].…”

The regulatory roles and mechanisms of the transcription factor FOXF2 in human diseases

“…Shh, the Hh ligand secreted from the pulmonary epithelium, is an important paracrine signal between the epithelium and the pulmonary vascular network, and it can promote VEGF and angiogenin production ( Zavala et al, 2017 ). Shh signaling is essential for craniofacial development ( Chiang et al, 1996 ).…”

“…Gorlin syndrome (Smith et al, 2014), basal cell carcinoma (Gutzmer & Solomon, 2019), medulloblastoma (Tamayo-Orrego & Charron, 2019), and digestive and respiratory tumors all involve Hh signaling (Wang et al, 2013). Shh, the Hh ligand secreted from the pulmonary epithelium, is an important paracrine signal between the epithelium and the pulmonary vascular network, and it can promote VEGF and angiogenin production (Zavala et al, 2017). Shh signaling is essential for craniofacial development (Chiang et al, 1996).…”