Effects of interleukin-17 on mouse bone marrow-derived mesenchymal stem cells in vitro

Abstract

Mesenchymal stem cells (MSCs) are multipotent adult stem cells that are found in many tissues where they play an important role in maintaining the tissue homeostasis. Due to their enormous potential in tissue regeneration, regulation of hematopoiesis, and immunomodulation, as well as the fact that they are readily available from numerous adult and perinatal tissues, MSCs have been in the focus of basic and clinical research in the last few decades. Although a significant and rapid progress in understanding the nature, various functions, and mechanisms of action of MSCs has been made during the last decade, we are still far from resolving some of the key issues that are necessary for their effective and safe use in the clinics. The importance of the local microenvironment in directing MSCs to perform their numerous and often conflicting functions have been increasingly recognized over the recent years. Interleukin-17 (IL-17) is a pleiotropic cytokine with important roles in many physiological and pathological processes, such as inflammation, immune response, and regulation of hematopoiesis. This cytokine achieves its functions indirectly, by modulating the expression of variety of soluble and membrane-bound factors in stromal cells. Although some effects of IL-17 on the proliferation and differentiation of MSCs have been demonstrated in human and mouse models, other potential effects, such as the influence of this cytokine on the regulatory role of MSCs in hematopoiesis and immune response, as well as the mechanisms and the significance of its action, are not sufficiently elucidated. The aim of this study was to isolate and characterize MSCs from mouse bone marrow (mBM-MSCs) and to analyze the effects of IL-17 on their phenotype, multilineage differentiation, proliferation, hematopoietic supportive capacity, and immunomodulatory activity. The mechanisms of action, including the signaling pathways and the role of NO as a mediator, were also examined...

Mezenhimske matične ćelije (MSC) pripadaju populaciji multipotentnih adultnih matičnih ćelija koje se nalaze u mnogim tkivima gde ostvaruju važne uloge u održavanju homeostaze. Zahvaljujući višestrukom potencijalu u regeneraciji tkiva, regulaciji hematopoeze i imunomodulaciji, kao i relativno lakoj dostupnosti iz raznih adultnih i perinatalnih tkiva, intenzivirana su istraživanja kako osnovne biologije MSC, tako i ona usmerena ka mogućnosti njihove terapijske primene. Iako je u poslednjoj deceniji došlo do značajnog i brzog napretka u razumevanju njihove prirode, raznovrsnih funkcija i mehanizama njihovog delovanja, još smo daleko od rasvetljavanja nekih osnovnih pitanja ključnih za njihovu efikasnu i bezbednu kliničku primenu. Poslednjih godina se sve više uviđa značaj lokalne mikrosredine u usmeravanju MSC ka obavljanju mnogobrojnih i često suprotstavljenih funkcija. Interleukin-17 (IL-17) je plejotropni citokin sa značajnim ulogama u mnogim fiziološkim i patološkim procesima organizma, poput inflamacije, imunskog odgovora i regulacije hematopoeze. IL-17 svoje efekte ostvaruje uglavnom indirektno, delujući na stromalne ćelije, modulišući u njima ekspresiju različitih solubilnih i membranskih faktora. Iako su istraživanja uticaja IL-17 na proliferaciju i diferencijacju humanih i mišjih MSC započeta, mnogi efekti, poput uticaja na regulatornu ulogu ovih ćelija u hematopoezi i imunskom odgovoru, kao i mehanizmi i značaj njegovog delovanja na MSC, još nisu dovoljno ispitani. Cilj ovog istraživanja bio je da se izoluju i okarakterišu MSC iz kostne srži miša (mBM-MSC) i utvrdi efekat IL-17 na fenotipske karakteristike, sposobnost višelinijske diferencijacije, proliferaciju, kapacitet podržavanja hematopoeze i imunomodulatorne sposobnosti ovih ćelija. Takođe, ispitivani su i mehanizami delovanja IL-17 na 8 mBM-MSC, uključujući aktivaciju signalnih puteva i ulogu NO kao posrednika u ovim efektima...