TY - JOUR

T1 - Role of AMP-activated protein kinase in regulating hypoxic survival and proliferation of mesenchymal stem cells

AU - De Meester, Carole

AU - Timmermans, Aurélie D.

AU - Balteau, Magali

AU - Ginion, Audrey

AU - Roelants, Véronique

AU - Noppe, Gauthier

AU - Porporato, Paolo E.

AU - Sonveaux, Pierre

AU - Viollet, Benoît

AU - Sakamoto, Kei

AU - Feron, Olivier

AU - Horman, Sandrine

AU - Vanoverschelde, Jean Louis

AU - Beauloye, Christophe

AU - Bertrand, Luc

PY - 2014/1/1

Y1 - 2014/1/1

N2 - AimsMesenchymal stem cells (MSCs) are widely used for cell therapy, particularly for the treatment of ischaemic heart disease. Mechanisms underlying control of their metabolism and proliferation capacity, critical elements for their survival and differentiation, have not been fully characterized. AMP-activated protein kinase (AMPK) is a key regulator known to metabolically protect cardiomyocytes against ischaemic injuries and, more generally, to inhibit cell proliferation. We hypothesized that AMPK plays a role in control of MSC metabolism and proliferation.Methods and resultsMSCs isolated from murine bone marrow exclusively expressed the AMPK1 catalytic subunit. In contrast to cardiomyocytes, a chronic exposure of MSCs to hypoxia failed to induce cell death despite the absence of AMPK activation. This hypoxic tolerance was the consequence of a preference of MSC towards glycolytic metabolism independently of oxygen availability and AMPK signalling. On the other hand, A-769662, a well-characterized AMPK activator, was able to induce a robust and sustained AMPK activation. We showed that A-769662-induced AMPK activation inhibited MSC proliferation. Proliferation was not arrested in MSCs derived from AMPK1-knockout mice, providing genetic evidence that AMPK is essential for this process. Among AMPK downstream targets proposed to regulate cell proliferation, we showed that neither the p70 ribosomal S6 protein kinase/eukaryotic elongation factor 2-dependent protein synthesis pathway nor p21 was involved, whereas p27 expression was increased by A-769662. Silencing p27 expression partially prevented the A-769662-dependent inhibition of MSC proliferation.ConclusionMSCs resist hypoxia independently of AMPK whereas chronic AMPK activation inhibits MSC proliferation, p27 being involved in this regulation.

AB - AimsMesenchymal stem cells (MSCs) are widely used for cell therapy, particularly for the treatment of ischaemic heart disease. Mechanisms underlying control of their metabolism and proliferation capacity, critical elements for their survival and differentiation, have not been fully characterized. AMP-activated protein kinase (AMPK) is a key regulator known to metabolically protect cardiomyocytes against ischaemic injuries and, more generally, to inhibit cell proliferation. We hypothesized that AMPK plays a role in control of MSC metabolism and proliferation.Methods and resultsMSCs isolated from murine bone marrow exclusively expressed the AMPK1 catalytic subunit. In contrast to cardiomyocytes, a chronic exposure of MSCs to hypoxia failed to induce cell death despite the absence of AMPK activation. This hypoxic tolerance was the consequence of a preference of MSC towards glycolytic metabolism independently of oxygen availability and AMPK signalling. On the other hand, A-769662, a well-characterized AMPK activator, was able to induce a robust and sustained AMPK activation. We showed that A-769662-induced AMPK activation inhibited MSC proliferation. Proliferation was not arrested in MSCs derived from AMPK1-knockout mice, providing genetic evidence that AMPK is essential for this process. Among AMPK downstream targets proposed to regulate cell proliferation, we showed that neither the p70 ribosomal S6 protein kinase/eukaryotic elongation factor 2-dependent protein synthesis pathway nor p21 was involved, whereas p27 expression was increased by A-769662. Silencing p27 expression partially prevented the A-769662-dependent inhibition of MSC proliferation.ConclusionMSCs resist hypoxia independently of AMPK whereas chronic AMPK activation inhibits MSC proliferation, p27 being involved in this regulation.

KW - AMPK

KW - Glycolysis

KW - Hypoxia

KW - Mesenchymal stem cells

KW - Proliferation

UR - http://www.scopus.com/inward/record.url?scp=84891352333&partnerID=8YFLogxK

U2 - 10.1093/cvr/cvt227

DO - 10.1093/cvr/cvt227

M3 - Journal article

C2 - 24104879

AN - SCOPUS:84891352333

VL - 101

SP - 20

EP - 29

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 1

ER -