Transglutaminase 2 Prevents Premature Senescence and Promotes Osteoblastic Differentiation of Mesenchymal Stem Cells through NRF2 Activation
Transglutaminase 2 (TG2) is a multifunctional enzyme that exhibits transamidase, GTPase, kinase, and protein disulfide isomerase (PDI) activities. Of these, transamidase-mediated modification of proteins regulates apoptosis, differentiation, inflammation, and fibrosis. TG2 is highly expressed in mes...
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Wiley
2023-01-01
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| Series: | Stem Cells International |
| Online Access: | http://dx.doi.org/10.1155/2023/8815888 |
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| author | Soo-Jin Lee Ji-Woong Shin Mee-Ae Kwon Ki Baek Lee Hyo-Jun Kim Jin-Haeng Lee Heun-Soo Kang Jong Kwan Jun Sung-Yup Cho In-Gyu Kim |
| author_facet | Soo-Jin Lee Ji-Woong Shin Mee-Ae Kwon Ki Baek Lee Hyo-Jun Kim Jin-Haeng Lee Heun-Soo Kang Jong Kwan Jun Sung-Yup Cho In-Gyu Kim |
| author_sort | Soo-Jin Lee |
| collection | DOAJ |
| description | Transglutaminase 2 (TG2) is a multifunctional enzyme that exhibits transamidase, GTPase, kinase, and protein disulfide isomerase (PDI) activities. Of these, transamidase-mediated modification of proteins regulates apoptosis, differentiation, inflammation, and fibrosis. TG2 is highly expressed in mesenchymal stem cells (MSCs) compared with differentiated cells, suggesting a role of TG2 specific for MSC characteristics. In this study, we report a new function of TG2 in the regulation of MSC redox homeostasis. During in vitro MSC expansion, TG2 is required for cell proliferation and self-renewal by preventing premature senescence but has no effect on the expression of surface antigens and oxidative stress-induced cell death. Moreover, induction of differentiation upregulates TG2 that promotes osteoblastic differentiation. Molecular analyses revealed that TG2 mediates tert-butylhydroquinone, but not sulforaphane, -induced nuclear factor erythroid 2-related factor 2 (NRF2) activation in a transamidase activity-independent manner. Differences in the mechanism of action between two NRF2 activators suggest that PDI activity of TG2 may be implicated in the stabilization of NRF2. The role of TG2 in the regulation of antioxidant response was further supported by transcriptomic analysis of MSC. These results indicate that TG2 is a critical enzyme in eliciting antioxidant response in MSC through NRF2 activation, providing a target for optimizing MSC manufacturing processes to prevent premature senescence. |
| format | Article |
| id | doaj-art-7f0e2b0081ec42d3a1188d609768ced9 |
| institution | Kabale University |
| issn | 1687-9678 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Stem Cells International |
| spelling | doaj-art-7f0e2b0081ec42d3a1188d609768ced92025-08-20T03:35:40ZengWileyStem Cells International1687-96782023-01-01202310.1155/2023/8815888Transglutaminase 2 Prevents Premature Senescence and Promotes Osteoblastic Differentiation of Mesenchymal Stem Cells through NRF2 ActivationSoo-Jin Lee0Ji-Woong Shin1Mee-Ae Kwon2Ki Baek Lee3Hyo-Jun Kim4Jin-Haeng Lee5Heun-Soo Kang6Jong Kwan Jun7Sung-Yup Cho8In-Gyu Kim9Department of Biochemistry and Molecular BiologyDepartment of Biochemistry and Molecular BiologyDepartment of Biochemistry and Molecular BiologyDepartment of Biochemistry and Molecular BiologyDepartment of Biochemistry and Molecular BiologyDepartment of Biochemistry and Molecular BiologyLaboratory for Cellular Response to Oxidative StressDepartment of Obstetrics and GynecologyDepartment of Biochemistry and Molecular BiologyDepartment of Biochemistry and Molecular BiologyTransglutaminase 2 (TG2) is a multifunctional enzyme that exhibits transamidase, GTPase, kinase, and protein disulfide isomerase (PDI) activities. Of these, transamidase-mediated modification of proteins regulates apoptosis, differentiation, inflammation, and fibrosis. TG2 is highly expressed in mesenchymal stem cells (MSCs) compared with differentiated cells, suggesting a role of TG2 specific for MSC characteristics. In this study, we report a new function of TG2 in the regulation of MSC redox homeostasis. During in vitro MSC expansion, TG2 is required for cell proliferation and self-renewal by preventing premature senescence but has no effect on the expression of surface antigens and oxidative stress-induced cell death. Moreover, induction of differentiation upregulates TG2 that promotes osteoblastic differentiation. Molecular analyses revealed that TG2 mediates tert-butylhydroquinone, but not sulforaphane, -induced nuclear factor erythroid 2-related factor 2 (NRF2) activation in a transamidase activity-independent manner. Differences in the mechanism of action between two NRF2 activators suggest that PDI activity of TG2 may be implicated in the stabilization of NRF2. The role of TG2 in the regulation of antioxidant response was further supported by transcriptomic analysis of MSC. These results indicate that TG2 is a critical enzyme in eliciting antioxidant response in MSC through NRF2 activation, providing a target for optimizing MSC manufacturing processes to prevent premature senescence.http://dx.doi.org/10.1155/2023/8815888 |
| spellingShingle | Soo-Jin Lee Ji-Woong Shin Mee-Ae Kwon Ki Baek Lee Hyo-Jun Kim Jin-Haeng Lee Heun-Soo Kang Jong Kwan Jun Sung-Yup Cho In-Gyu Kim Transglutaminase 2 Prevents Premature Senescence and Promotes Osteoblastic Differentiation of Mesenchymal Stem Cells through NRF2 Activation Stem Cells International |
| title | Transglutaminase 2 Prevents Premature Senescence and Promotes Osteoblastic Differentiation of Mesenchymal Stem Cells through NRF2 Activation |
| title_full | Transglutaminase 2 Prevents Premature Senescence and Promotes Osteoblastic Differentiation of Mesenchymal Stem Cells through NRF2 Activation |
| title_fullStr | Transglutaminase 2 Prevents Premature Senescence and Promotes Osteoblastic Differentiation of Mesenchymal Stem Cells through NRF2 Activation |
| title_full_unstemmed | Transglutaminase 2 Prevents Premature Senescence and Promotes Osteoblastic Differentiation of Mesenchymal Stem Cells through NRF2 Activation |
| title_short | Transglutaminase 2 Prevents Premature Senescence and Promotes Osteoblastic Differentiation of Mesenchymal Stem Cells through NRF2 Activation |
| title_sort | transglutaminase 2 prevents premature senescence and promotes osteoblastic differentiation of mesenchymal stem cells through nrf2 activation |
| url | http://dx.doi.org/10.1155/2023/8815888 |
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