TY - JOUR
T1 - Inactivated mesenchymal stem cells maintain immunomodulatory capacity
AU - Luk, Franka
AU - De Witte, Samantha F.H.
AU - Korevaar, Sander S.
AU - Roemeling-Van Rhijn, Marieke
AU - Franquesa, Marcella
AU - Strini, Tanja
AU - Van Den Engel, Sandra
AU - Gargesha, Madhusudhana
AU - Roy, Debashish
AU - Dor, Frank J.M.F.
AU - Horwitz, Edwin M.
AU - De Bruin, Ron W.F.
AU - Betjes, Michiel G.H.
AU - Baan, Carla C.
AU - Hoogduijn, Martin J.
N1 - Publisher Copyright: © Mary Ann Liebert, Inc. 2016.
PY - 2016/9/15
Y1 - 2016/9/15
N2 - Mesenchymal stem cells (MSC) are studied as a cell therapeutic agent for treatment of various immune diseases. However, therapy with living culture-expanded cells comes with safety concerns. Furthermore, development of effective MSC immunotherapy is hampered by lack of knowledge of the mechanisms of action and the therapeutic components of MSC. Such knowledge allows better identification of diseases that are responsive to MSC treatment, optimization of the MSC product, and development of therapy based on functional components of MSC. To close in on the components that carry the therapeutic immunomodulatory activity of MSC, we generated MSC that were unable to respond to inflammatory signals or secrete immunomodulatory factors, but preserved their cellular integrity [heat-inactivated MSC (HI-MSC)]. Secretome-deficient HI-MSC and control MSC showed the same biodistribution and persistence after infusion in mice with ischemic kidney injury. Both control and HI-MSC induced mild inflammatory responses in healthy mice and dramatic increases in interleukin-10, and reductions in interferon gamma levels in sepsis mice. In vitro experiments showed that opposite to control MSC, HI-MSC lacked the capability to suppress T-cell proliferation or induce regulatory B-cell formation. However, both HI-MSC and control MSC modulated monocyte function in response to lipopolysaccharides. The results of this study demonstrate that, in particular disease models, the immunomodulatory effect of MSC does not depend on their secretome or active cross-talk with immune cells, but on recognition of MSC by monocytic cells. These findings provide a new view on MSC-induced immunomodulation and help identify key components of the therapeutic effects of MSC.
AB - Mesenchymal stem cells (MSC) are studied as a cell therapeutic agent for treatment of various immune diseases. However, therapy with living culture-expanded cells comes with safety concerns. Furthermore, development of effective MSC immunotherapy is hampered by lack of knowledge of the mechanisms of action and the therapeutic components of MSC. Such knowledge allows better identification of diseases that are responsive to MSC treatment, optimization of the MSC product, and development of therapy based on functional components of MSC. To close in on the components that carry the therapeutic immunomodulatory activity of MSC, we generated MSC that were unable to respond to inflammatory signals or secrete immunomodulatory factors, but preserved their cellular integrity [heat-inactivated MSC (HI-MSC)]. Secretome-deficient HI-MSC and control MSC showed the same biodistribution and persistence after infusion in mice with ischemic kidney injury. Both control and HI-MSC induced mild inflammatory responses in healthy mice and dramatic increases in interleukin-10, and reductions in interferon gamma levels in sepsis mice. In vitro experiments showed that opposite to control MSC, HI-MSC lacked the capability to suppress T-cell proliferation or induce regulatory B-cell formation. However, both HI-MSC and control MSC modulated monocyte function in response to lipopolysaccharides. The results of this study demonstrate that, in particular disease models, the immunomodulatory effect of MSC does not depend on their secretome or active cross-talk with immune cells, but on recognition of MSC by monocytic cells. These findings provide a new view on MSC-induced immunomodulation and help identify key components of the therapeutic effects of MSC.
UR - http://www.scopus.com/inward/record.url?scp=84987749772&partnerID=8YFLogxK
U2 - https://doi.org/10.1089/scd.2016.0068
DO - https://doi.org/10.1089/scd.2016.0068
M3 - Article
C2 - 27349989
SN - 1547-3287
VL - 25
SP - 1342
EP - 1354
JO - Stem cells and development
JF - Stem cells and development
IS - 18
ER -