TY - JOUR
T1 - The Autophagy Protein Pacer Positively Regulates the Therapeutic Potential of Mesenchymal Stem Cells in a Mouse Model of DSS-Induced Colitis
AU - Bergmann, Cristian A.
AU - Beltran, Sebastian
AU - Vega-Letter, Ana Maria
AU - Murgas, Paola
AU - Hernandez, Maria Fernanda
AU - Gomez, Laura
AU - Labrador, Luis
AU - Cortés, Bastián I.
AU - Poblete, Cristian
AU - Quijada, Cristobal
AU - Carrion, Flavio
AU - Woehlbier, Ute
AU - Manque, Patricio A.
N1 - Funding Information:
Funding: This work was funded by Anillo project ACT1109 (P.A.M.), FONDECYT Regular 1150743 (U.W.), Fondo Puente PEP-I-2019054 (U.W.), FONDECYT Regular 1200459 (U.W.), FONDECYT Initiation 11190258 (P.M.).
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/4/30
Y1 - 2022/4/30
N2 - Mesenchymal stem cells (MSC) have emerged as a promising tool to treat inflammatory diseases, such as inflammatory bowel disease (IBD), due to their immunoregulatory properties. Frequently, IBD is modeled in mice by using dextran sulfate sodium (DSS)-induced colitis. Recently, the modulation of autophagy in MSC has been suggested as a novel strategy to improve MSC-based immunotherapy. Hence, we investigated a possible role of Pacer, a novel autophagy enhancer, in regulating the immunosuppressive function of MSC in the context of DSS-induced colitis. We found that Pacer is upregulated upon stimulation with the pro-inflammatory cytokine TNFα, the main cytokine released in the inflammatory environment of IBD. By modulating Pacer expression in MSC, we found that Pacer plays an important role in regulating the autophagy pathway in this cell type in response to TNFα stimulation, as well as in regulating the immunosuppressive ability of MSC toward T-cell proliferation. Furthermore, increased expression of Pacer in MSC enhanced their ability to ameliorate the symptoms of DSS-induced colitis in mice. Our results support previous findings that autophagy regulates the therapeutic potential of MSC and suggest that the augmentation of autophagic capacity in MSC by increasing Pacer levels may have therapeutic implications for IBD.
AB - Mesenchymal stem cells (MSC) have emerged as a promising tool to treat inflammatory diseases, such as inflammatory bowel disease (IBD), due to their immunoregulatory properties. Frequently, IBD is modeled in mice by using dextran sulfate sodium (DSS)-induced colitis. Recently, the modulation of autophagy in MSC has been suggested as a novel strategy to improve MSC-based immunotherapy. Hence, we investigated a possible role of Pacer, a novel autophagy enhancer, in regulating the immunosuppressive function of MSC in the context of DSS-induced colitis. We found that Pacer is upregulated upon stimulation with the pro-inflammatory cytokine TNFα, the main cytokine released in the inflammatory environment of IBD. By modulating Pacer expression in MSC, we found that Pacer plays an important role in regulating the autophagy pathway in this cell type in response to TNFα stimulation, as well as in regulating the immunosuppressive ability of MSC toward T-cell proliferation. Furthermore, increased expression of Pacer in MSC enhanced their ability to ameliorate the symptoms of DSS-induced colitis in mice. Our results support previous findings that autophagy regulates the therapeutic potential of MSC and suggest that the augmentation of autophagic capacity in MSC by increasing Pacer levels may have therapeutic implications for IBD.
KW - KIAA0226L
KW - PACER
KW - RUBCNL
KW - autophagy
KW - colitis
KW - inflammatory bowel disease
KW - mesenchymal stem cells
KW - therapy
UR - http://www.scopus.com/inward/record.url?scp=85129145978&partnerID=8YFLogxK
U2 - 10.3390/cells11091503
DO - 10.3390/cells11091503
M3 - Article
C2 - 35563809
AN - SCOPUS:85129145978
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 9
M1 - 1503
ER -