Conditioning of Mesenchymal Stromal Cells With mTOR Inhibitor Enhances Regenerative Properties of Secretome and Attenuates Vascular Calcification
1Clinic for Nephrology and Intensive Care Medicine, Charité
University Hospital, Berlin, Germany
2Department of Cell and Gene Therapy, University Medical Center Eppendorf, Hamburg, Germany.
Meeting: 2015 American Transplant Congress
Abstract number: A168
Keywords: Post-transplant diabetes, Sirolimus (SLR), Stem cells, Vascular disease
Session Information
Session Name: Poster Session A: Kidney: Cardiovascular and Metabolic
Session Type: Poster Session
Date: Saturday, May 2, 2015
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Exhibit Hall E
Similar to patients with chronic kidney disease, recipients of kidney transplants are a high-risk population for cardiovascular events due to arterial media calcification in particular when post-transplant diabetes mellitus (PTDM) develops. Exhaustion of regenerative capacity of vascular smooth muscle cells (VSMC) and their progenitors results in osteoblast like VSMC transformation and calcification. We hypothesized that targeting paracrine properties of mesenchymal stromal cells (MSC) can boost their regenerative potential and mitigate the calcification process. We addressed a pleiotropic therapeutic potential of the rapamycin on the regenerative capacity of MSC since it modulates the mTOR-network, a glucose sensitive master regulator of cell differentiation and cell fate programs.
Osteoblastic transformation was induced in human coronary artery VSMC with high calcium and phosphate and calcitriol. Conditioned media from MSC or VSMC control was transferred to calcifying VSMC. Feeder (MSC or VSMC) and receiver cells (VSMC) were cultured under normal or high glucose conditions. Anti-diabetics with influence on mTOR signaling (metformin, insulin) or rapamycin were added.
MSC conditioned medium markedly reduced osteoblastic transformation of VSMC. High glucose had no influence on VSMC calcification. Treatment of feeder-MSC with rapamycin boosted the anti-calcifying properties of the MSC secretome with normal and high glucose. Addition of metformin was also beneficial but only in combination with high glucose. Insulin was not protective. Signal transduction analyses revealed substance specific signaling patterns of the mTOR network in calcifying VSMC. Rapamycin and metformin reduced cellular senescence and enhanced autophagy as demonstrated by western blots for p16INK4a and LC3B. Lack of protection observed with insulin was reflected by increased senescence, reduced autophagy and elevated apoptosis (cleaved caspase 3).
MSC secrete factors capable of protecting VSMC from osteoblastic transformation. Modulation of mTOR signaling with rapamycin or metformin enhances regenerative properties of the MSC secretome by induction of protective cell fate programs. Our findings may imply novel preventative strategies against vascular complications in transplant recipients with PTDM.
To cite this abstract in AMA style:
Hegner B, Kurth C, Schaub T, Lange C, Dragun D. Conditioning of Mesenchymal Stromal Cells With mTOR Inhibitor Enhances Regenerative Properties of Secretome and Attenuates Vascular Calcification [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/conditioning-of-mesenchymal-stromal-cells-with-mtor-inhibitor-enhances-regenerative-properties-of-secretome-and-attenuates-vascular-calcification/. Accessed November 21, 2024.« Back to 2015 American Transplant Congress