Regulatory role of sphingosine kinase and sphingosine-1-phosphate receptor signaling in progenitor/stem cells

Abstract

Balanced sphingolipid signaling is important for the maintenance of homeostasis. Sphingolipids were demonstrated to function as structural components, second messengers, and regulators of cell growth and survival in normal and disease-affected tissues. Particularly, sphingosine kinase 1 (SphK1) and its product sphingosine-1-phosphate (S1P) operate as mediators and facilitators of proliferation-linked signaling. Unlimited proliferation (self-renewal) within the regulated environment is a hallmark of progenitor/stem cells that was recently associated with the S1P signaling network in vasculature, nervous, muscular, and immune systems. S1P was shown to regulate progenitor-related characteristics in normal and cancer stem cells (CSCs) via G-protein coupled receptors S1Pn (n = 1 to 5). The SphK/S1P axis is crucially involved in the regulation of embryonic development of vasculature and the nervous system, hematopoietic stem cell migration, regeneration of skeletal muscle, and development of multiple sclerosis. The ratio of the S1P receptor expression, localization, and specific S1P receptor-activated downstream effectors influenced the rate of self-renewal and should be further explored as regeneration-related targets. Considering malignant transformation, it is essential to control the level of self-renewal capacity. Proliferation of the progenitor cell should be synchronized with differentiation to provide healthy lifelong function of blood, immune systems, and replacement of damaged or dead cells. The differentiation-related role of SphK/S1P remains poorly assessed. A few pioneering investigations explored pharmacological tools that target sphingolipid signaling and can potentially confine and direct self-renewal towards normal differentiation. Further investigation is required to test the role of the SphK/S1P axis in regulation of self-renewal and differentiation.

Sphingosine‐1‐phosphate (S1P) receptors: Promising drug targets for treating bone‐related diseases

“…A better understanding of S1P in osteoclastic/osteoblastic cells, as well as related signal pathways, is in great demand 55 . In addition to the role of S1P as a first or second messenger that regulates cell migration, differentiation, proliferation and apoptosis, we focused on osteoclast‐osteoblast crosstalk coupled with S1P 92 . Interestingly, FTY720 acts as an inhibitor of the S1P receptor and was tested in clinical experiments in 2017 93 .…”

SphK2/S1P promotes metastasis in triple negative breast cancer through PAK1/LIMK1/Cofilin1 signaling pathway

“…Accumulating evidence demonstrates that S1P is a critical second messenger that regulates the migration of various cells, not only cancer cells [25,26] but also myofibroblasts [27], dendritic cells [28] and stem cells [29]. Moreover, it has been reported that S1P generated from SphK1 accelerated breast cancer cell migration [30].…”

Mesenchymal Stem Cell Derived Extracellular Vesicles for Tissue Engineering and Regenerative Medicine Applications

“…Moreover, human iPSC-EVs enhanced hepatic regeneration in hepatic ischemia-reperfusion injury rat models, by inhibiting apoptosis of hepatic cells, suppressing inflammatory responses, and attenuating the oxidative stress response [134]. Human iPSC-EVs were also reported to induce hepatocyte proliferation in vitro and in vivo in a dose-dependent manner, which is related to the activation of sphingosine kinase and sphingosine-1-phosphate signalling pathway [135], known to promote cell proliferation in various cell types [136][137][138]. Similarly, treatment with human UCMSC-EVs has been shown to ameliorate the infiltration of neutrophils and diminish oxidative stress in hepatic tissue; therefore protecting against hepatic apoptosis [139].…”