Finnish Red Cross Blood Service R&D has a long history of studying the therapeutic efficacy and targeting of MSCs using both in vitro and in vivo models (e.g. Nystedt et al. Stem Cells 2013; Kilpinen et al. JEV 2013; Kerkelä et al. Stem Cells Transl Med 2013; Kilpinen et al. JLR 2013; Mitkari et al. Behav Brain Res 2014; Mitkari et al. J Cereb Blood Flow Metab 2015; Khabbal et al. Cell Transplant 2015; Cui et al. Stem Cell Res Ther 2015).
MSCs have the capacity to counteract excessive inflammatory responses. MSCs possess a range of immunomodulatory mechanisms, which can be deployed in response to signals in a particular environment and in concert with other immune cells. One not yet well-known mechanism of immunosuppression of human MSCs involves ectonucleotidase CD73, known as an immunophenotypic marker of MSCs, which together with ectonucleotidase CD39 generates immunosuppressive adenosine from pro-inflammatory ATP via the intermediates ADP and AMP. Our studies have shown that adenosinergic signaling is an important immunoregulatory mechanism of MSCs, especially in situations where pro-inflammatory ATP is present in the extracellular environment, like in tissue injury. The efficient production of adenosine is dependent on the concerted action of CD39-positive immune cells with CD73-positive cells, such as MSCs or MSC-derived extracellular vesicles (MSC-EVs) (Kerkelä et al. Stem Cells, in press 2015). We have also shown that MSC-EVs have a therapeutic effect in acute kidney injury model (Kilpinen et al. JEV 2013).
Another mechanism we are studying is the role of bioactive lipid mediators in MSC immunomodulation. Our previous studies have shown that fatty acid composition of the BM MSC membranes changes during aging/senescence. Especially the polyunsaturated fatty acid (PUFA) n-6/n-3 ratio is increased which reflects more pro-inflammatory type of changes, confirmed also with an immunosuppressive in vitro assay (Kilpinen et al. JLR 2013). These fatty acids are precursors for so called specialized pro-resolving lipid mediators (SPMs), including lipoxins, resolvins, and maresins, which are important regulators in the resolution phase of inflammation. With the supplementation of specific PUFAs in vitro we are able to specifically change the membrane fatty acid composition and ratio between n-6/n-3 PUFAs (Tigistu-Sahle et al. unpublished results). According to our hypothesis, PUFA composition in the membranes may have a direct effect on the anti-inflammatory properties of BM MSCs and lead to the production of different bioactive lipids. These could in turn have effects on immune cells, such as macrophages and T cells, and ultimately in resolution of inflammation.
Saara Laitinen, PhD
Erja Kerkelä, PhD, Adj. Prof.
Kati Hyvärinen, PhD
Lotta Kilpinen, MSc, PhD Student
Minna Holopainen, MSc, PhD Student
Lotta Sankkila, MSc, technician
University of Helsinki, Department of Biosciences, Physiology and Neuroscience, Helsinki University Lipidomics Unit
Reijo Käkelä, PhD, Adj. Prof.
Feven Tigistu-Sahle, MSc, PhD Student
University of Helsinki, Department of Biosciences, Division of Biochemistry and Biotechnology, EV Group
Pia Siljander, PhD, Adj. Prof.
Maarit Takatalo, PhD
Sami Valkonen, MSc, PhD student
Kerkelä E, Laitinen A, Räbinä J, Valkonen S, Takatalo M, Larjo A, Veijola J, Lampinen M, Siljander P, Lehenkari P, Alfthan K, Laitinen S. Adenosinergic immunosuppression by human mesenchymal stromal cells (MSCs) requires co-operation with T cells. Stem Cells 2015, in press.
Kilpinen L, Tigistu-Sahle F, Oja S, Greco D, Parmar A, Saavalainen PA, Nikkilä J, Korhonen M, Lehenkari P, Käkelä R and Laitinen S. Aging Bone Marrow Mesenchymal Stromal Cells Have Altered Membrane Glycerophospholipid Composition and Functionality. J Lipid Res. 2013;54(3):622-35. PM: 23271708
Kilpinen L, Impola U, Sankkila L, Ritamo I, Aatonen M, Kilpinen S, Tuimala J, Valmu L, Levijoki J, Finckenberg P, Siljander P, Kankuri E, Mervaala E and Laitinen S. Extracellular membrane vesicles form umbilical cord blood-derived MSC protect against ischemic acute kidney injury, a feature that is lost after inflammatory conditioning. J Extracellular Vehicles 2013;2:21927. PM: 24349659
Kerkelä E, Hakkarainen T, Mäkelä T, Raki M, Kambur O, Kilpinen L, Nikkilä J, Lehtonen S, Ritamo I, Pernu R, Pietilä M, Takalo R, Juvonen T, Bergström K, Kalso E, Valmu L, Laitinen S, Lehenkari P, Nystedt J. Transient Proteolytic Modification of Mesenchymal Stromal Cells Increases Lung Clearance Rate and Targeting to Injured Tissue. Stem Cells Transl Med 2013;2(7):510-10. PM: 23734061