caa a22 4500 605543895 CHVBK 20210128100929.0 cr unu---uuuuu 210128e20150201xx s 000 0 eng 10.1007/s00109-014-1218-2 doi (NATIONALLICENCE)springer-10.1007/s00109-014-1218-2 Modulation of cellular stress response via the erythropoietin/CD131 heteroreceptor complex in mouse mesenchymal-derived cells [Elektronische Daten] [Stefan Bohr, Suraj Patel, Radovan Vasko, Keyue Shen, Arvin Iracheta-Vellve, Jungwoo Lee, Shyam Bale, Nilay Chakraborty, Michael Brines, Anthony Cerami, Francois Berthiaume, Martin Yarmush] Tissue-protective properties of erythropoietin (EPO) have let to the discovery of an alternative EPO signaling via an EPO-R/CD131 receptor complex which can now be specifically targeted through pharmaceutically designed short sequence peptides such as ARA290. However, little is still known about specific functions of alternative EPO signaling in defined cell populations. In this study, we investigated effects of signaling through EPO-R/CD131 complex on cellular stress responses and pro-inflammatory activation in different mesenchymal-derived phenotypes. We show that anti-apoptotic, anti-inflammatory effects of ARA290 and EPO coincide with the externalization of CD131 receptor component as an immediate response to cellular stress. In addition, alternative EPO signaling strongly modulated transcriptional, translational, or metabolic responses after stressor removal. Specifically, we saw that ARA290 was able to overcome a TNFα-mediated inhibition of transcription factor activation related to cell stress responses, most notably of serum response factor (SRF), heat shock transcription factor protein 1 (HSF1), and activator protein 1 (AP1). We conclude that alternative EPO signaling acts as a modulator of pro-inflammatory signaling pathways and likely plays a role in restoring tissue homeostasis. Key message: • Erythropoietin (EPO) triggers an alternative pathway via heteroreceptor EPO/CD131. • ARA290 peptide specifically binds EPO/CD131 but not the canonical EPO/EPO receptor. • Oxidative stress and inflammation promote cell surface expression of CD131. • ARA290 prevents tumor necrosis factor-mediated inhibition of stress-related genes. • Alternative EPO signaling modulates inflammation and promotes tissue homeostasis. Springer-Verlag Berlin Heidelberg, 2014 ARA290 nationallicence Oxidative stress nationallicence Heat shock nationallicence Apoptosis nationallicence TNFα nationallicence Homeostasis nationallicence Mesenchymal stem cells nationallicence Bohr Stefan Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, 51 Blossom Street, 4th Floor, 02114, Boston, MA, USA aut Patel Suraj Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, 51 Blossom Street, 4th Floor, 02114, Boston, MA, USA aut Vasko Radovan Department of Medicine, New York Medical College, Valhalla, NY, USA aut Shen Keyue Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, 51 Blossom Street, 4th Floor, 02114, Boston, MA, USA aut Iracheta-Vellve Arvin Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, 51 Blossom Street, 4th Floor, 02114, Boston, MA, USA aut Lee Jungwoo Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, 51 Blossom Street, 4th Floor, 02114, Boston, MA, USA aut Bale Shyam Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, 51 Blossom Street, 4th Floor, 02114, Boston, MA, USA aut Chakraborty Nilay Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, 51 Blossom Street, 4th Floor, 02114, Boston, MA, USA aut Brines Michael Araim Pharmaceuticals, 10562, Ossining, NY, USA aut Cerami Anthony Araim Pharmaceuticals, 10562, Ossining, NY, USA aut Berthiaume Francois Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, 08854, Piscataway, NJ, USA aut Yarmush Martin Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, 51 Blossom Street, 4th Floor, 02114, Boston, MA, USA aut Journal of Molecular Medicine Springer Berlin Heidelberg 93/2(2015-02-01), 199-210 0946-2716 93:2<199 2015 93 109 https://doi.org/10.1007/s00109-014-1218-2 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00109-014-1218-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Bohr Stefan Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, 51 Blossom Street, 4th Floor, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Patel Suraj Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, 51 Blossom Street, 4th Floor, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Vasko Radovan Department of Medicine, New York Medical College, Valhalla, NY, USA aut NATIONALLICENCE 700 1- Shen Keyue Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, 51 Blossom Street, 4th Floor, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Iracheta-Vellve Arvin Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, 51 Blossom Street, 4th Floor, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Lee Jungwoo Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, 51 Blossom Street, 4th Floor, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Bale Shyam Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, 51 Blossom Street, 4th Floor, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Chakraborty Nilay Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, 51 Blossom Street, 4th Floor, 02114, Boston, MA, USA aut NATIONALLICENCE 700 1- Brines Michael Araim Pharmaceuticals, 10562, Ossining, NY, USA aut NATIONALLICENCE 700 1- Cerami Anthony Araim Pharmaceuticals, 10562, Ossining, NY, USA aut NATIONALLICENCE 700 1- Berthiaume Francois Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, 08854, Piscataway, NJ, USA aut NATIONALLICENCE 700 1- Yarmush Martin Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, 51 Blossom Street, 4th Floor, 02114, Boston, MA, USA aut NATIONALLICENCE 773 0- Journal of Molecular Medicine Springer Berlin Heidelberg 93/2(2015-02-01), 199-210 0946-2716 93:2<199 2015 93 109