Attenuation of cysteinyl leukotrienes induces human mesenchymal stem cell differentiation

Abstract

Although there are numerous investigations describing bone marrow cells or bone-marrow derived cells at the site of such injuries as bone fractures, infarction and subsequent ischemic reperfusion injury, or cutaneous wounds, little is know about the factors that affect the cells in those clinical situations. Cysteinyl leukotrienes have been extensively investigated in airway diseases that may eventually lead to lung fibrosis; while the engraftment of mesenchymal stem cells have been shown to reverse bleomycin-induced lung fibrosis in vivo. Therefore, we elucidated the involvement of cysteinyl leukotrienes in human mesenchymal stem cell proliferation and differentiation. Human mesenchymal stem cells express the cysteinyl leukotriene type 1 receptor. Various doses of pranlukast, which is a specific cysteinyl leukotriene type 1 receptor antagonist, failed to affect the proliferation of cells; however, 10(-6) M of pranlukast significantly induced cellular cytoplasmic differentiation by showing microvilli sprouting and the emersion of rough endoplasmic reticulum within a 16-hour(s) incubation. Additionally, pranlukast-induced fibronectin protein production by human mesenchymal stem cells. Therefore, attenuation of the cysteinyl leukotriene pathway contributes to human mesenchymal stem cell differentiation and may contribute to modulation of the local injury site.

Enhanced fracture repair by leukotriene antagonism is characterized by increased chondrocyte proliferation and early bone formation: A novel role of the cysteinyl LT‐1 receptor

“…For changes in enhancing chondrogenesis to be evident at day seven suggests an early and potent effect in promoting MSC differentiation, which is a consequence of inhibiting the effects of cysteinyl leukotrienes by either montelukast sodium or zileuton. Thus our findings during the fracture repair process are consistent with the in vitro data reported by Akino et al (2006). In the treatment animals, our data indicates an early and sustained increase in chondrocyte formation observed at both 7 and 10 days, suggesting part of the effect of these drugs may promote MSC differentiation to chondroid and osteoblast lineage cells that is further supported by our gene expression studies.…”

“…The cysteinyl leukotrienes in particular have been implicated as negative regulators of MSC differentiation (Akino et al, 2006). These findings are particularly interesting given the critical role of MSC differentiation to chondrocytes and osteoblasts required for successful fracture repair.…”

“…The cysteinyl leukotrienes as a group have previously been implicated as negative regulators of MSC differentiation (Akino et al, 2006). In vitro studies of human MSCs cultured in the presence of pranlukast, a specific cysteinyl leukotriene type 1 (CysLT1) receptor antagonist, showed enhanced cellular differentiation based on morphology, highlighting the potential inhibitory effect of the CysLT1 pathway on MSC differentiation.…”

“…Given the evidence that the CysLT1 receptor acts as a negative regulator of MSC differentiation (Akino et al, 2006), a process critical for fracture repair, along with previous murine fracture studies indicating larger callous size and enhanced mechanical properties of healing fractures in a 5-LO knockout model (Manigrasso and O’Connor, 2006), we hypothesized that oral medications which affect leukotriene synthesis could be used to enhance fracture repair. In the present study, we sought to determine potential mechanisms by which oral inhibition of the CysLT1 receptor alters the fracture repair response.…”

Effect of leukotriene D4 on mouse embryonic stem cell migration and proliferation: Involvement of PI3K/Akt as well as GSK‐3β/β‐catenin signaling pathways

“…Of particular interest is the use of fatty acid metabolites including prostacyclin, prostaglandin, thromboxane, and leukotrienes (LT). Cysteinyl leukotrienes (CysLTs), such as LTC 4 , LTD 4 , and LTE 4 , are derived from the ubiquitous membrane component arachidonic acid and are multipotential lipid mediators [Capra, 2004;Akino et al, 2006]. They play a key role in paracrine or autocrine regulations of embryonic and fetal functions, which are regulated by 5-lipoxygenase [Schafer et al, 1996;Sato et al, 2008].…”