TY - JOUR
T1 - Lactate
T2 - an alternative pathway for the immunosuppressive properties of mesenchymal stem/stromal cells
AU - Pradenas, Carolina
AU - Luque-Campos, Noymar
AU - Oyarce, Karina
AU - Contreras-Lopez, Rafael
AU - Bustamante-Barrientos, Felipe A.
AU - Bustos, Andrés
AU - Galvez-Jiron, Felipe
AU - Araya, María Jesús
AU - Asencio, Catalina
AU - Lagos, Raúl
AU - Herrera-Luna, Yeimi
AU - Abba Moussa, Daouda
AU - Hill, Charlotte Nicole
AU - Lara-Barba, Eliana
AU - Altamirano, Claudia
AU - Ortloff, Alexander
AU - Hidalgo-Fadic, Yessia
AU - Vega-Letter, Ana María
AU - García-Robles, María de los Ángeles
AU - Djouad, Farida
AU - Luz-Crawford, Patricia
AU - Elizondo-Vega, Roberto
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - Background: The metabolic reprogramming of mesenchymal stem/stromal cells (MSC) favoring glycolysis has recently emerged as a new approach to improve their immunotherapeutic abilities. This strategy is associated with greater lactate release, and interestingly, recent studies have proposed lactate as a functional suppressive molecule, changing the old paradigm of lactate as a waste product. Therefore, we evaluated the role of lactate as an alternative mediator of MSC immunosuppressive properties and its contribution to the enhanced immunoregulatory activity of glycolytic MSCs. Materials and methods: Murine CD4+ T cells from C57BL/6 male mice were differentiated into proinflammatory Th1 or Th17 cells and cultured with either L-lactate, MSCs pretreated or not with the glycolytic inductor, oligomycin, and MSCs pretreated or not with a chemical inhibitor of lactate dehydrogenase A (LDHA), galloflavin or LDH siRNA to prevent lactate production. Additionally, we validated our results using human umbilical cord-derived MSCs (UC-MSCs) in a murine model of delayed type 1 hypersensitivity (DTH). Results: Our results showed that 50 mM of exogenous L-lactate inhibited the proliferation rate and phenotype of CD4+ T cell-derived Th1 or Th17 by 40% and 60%, respectively. Moreover, the suppressive activity of both glycolytic and basal MSCs was impaired when LDH activity was reduced. Likewise, in the DTH inflammation model, lactate production was required for MSC anti-inflammatory activity. This lactate dependent-immunosuppressive mechanism was confirmed in UC-MSCs through the inhibition of LDH, which significantly decreased their capacity to control proliferation of activated CD4+ and CD8+ human T cells by 30%. Conclusion: These findings identify a new MSC immunosuppressive pathway that is independent of the classical suppressive mechanism and demonstrated that the enhanced suppressive and therapeutic abilities of glycolytic MSCs depend at least in part on lactate production.
AB - Background: The metabolic reprogramming of mesenchymal stem/stromal cells (MSC) favoring glycolysis has recently emerged as a new approach to improve their immunotherapeutic abilities. This strategy is associated with greater lactate release, and interestingly, recent studies have proposed lactate as a functional suppressive molecule, changing the old paradigm of lactate as a waste product. Therefore, we evaluated the role of lactate as an alternative mediator of MSC immunosuppressive properties and its contribution to the enhanced immunoregulatory activity of glycolytic MSCs. Materials and methods: Murine CD4+ T cells from C57BL/6 male mice were differentiated into proinflammatory Th1 or Th17 cells and cultured with either L-lactate, MSCs pretreated or not with the glycolytic inductor, oligomycin, and MSCs pretreated or not with a chemical inhibitor of lactate dehydrogenase A (LDHA), galloflavin or LDH siRNA to prevent lactate production. Additionally, we validated our results using human umbilical cord-derived MSCs (UC-MSCs) in a murine model of delayed type 1 hypersensitivity (DTH). Results: Our results showed that 50 mM of exogenous L-lactate inhibited the proliferation rate and phenotype of CD4+ T cell-derived Th1 or Th17 by 40% and 60%, respectively. Moreover, the suppressive activity of both glycolytic and basal MSCs was impaired when LDH activity was reduced. Likewise, in the DTH inflammation model, lactate production was required for MSC anti-inflammatory activity. This lactate dependent-immunosuppressive mechanism was confirmed in UC-MSCs through the inhibition of LDH, which significantly decreased their capacity to control proliferation of activated CD4+ and CD8+ human T cells by 30%. Conclusion: These findings identify a new MSC immunosuppressive pathway that is independent of the classical suppressive mechanism and demonstrated that the enhanced suppressive and therapeutic abilities of glycolytic MSCs depend at least in part on lactate production.
KW - Glycolytic metabolism
KW - Immunosuppression
KW - Lactate dehydrogenase, lactate
KW - Mesenchymal stem/stromal cells
KW - Th1 and Th17 cells
UR - http://www.scopus.com/inward/record.url?scp=85176954850&partnerID=8YFLogxK
U2 - 10.1186/s13287-023-03549-4
DO - 10.1186/s13287-023-03549-4
M3 - Article
C2 - 37981698
AN - SCOPUS:85176954850
SN - 1757-6512
VL - 14
SP - 1
EP - 14
JO - Stem Cell Research and Therapy
JF - Stem Cell Research and Therapy
IS - 1
M1 - 335
ER -