WP 1

Generating autologous blood vessels ready for clinical use in bypass surgery

Main Objective is to bioengineer blood vessels for bypass surgery in patients not having high quality vessel graft sources. In specific, we would like to recellularize bloodvessel scaffolds with easy accessible sources of stem cells and hereby generate autologous bloodvessels ready for clinical use in bypass surgery.

Background

GENERAL BACKGROUND An increasing population of diabetics and hypertensive patients suffer secondarily from cardiovascular disease (CVD) that in Denmark leads to 36% of all deaths [1]. Depending on the nature of CVD, either cardiac- or lower extremity function will be compromised, and the patient will die or be amputated without adequate reperfusion interventions. Reperfusing ischemic tissue includes insertion of a vein or artery from the chest or arm/leg onto the heart/leg re-directing blood around the occluded vessel. However, wound infection in the graft donor site is a frequent complication (25%), and several patient groups such as claudicants, diabetics, and patients with varices (20% of the Danish population) or vein disease have very limited graft material. Likewise, many Danish patients suffers from lower extremity ischemia, and a fraction of these experience severe peripheral ischemia, where surgeons has no other option than leg amputation. Synthetic conduits are readily available for large diameter vessel reconstruction, but quick collapse, in-grafts thrombosis, and infections decrease patency substantially of these materials and are therefore not used for small diameter blood vessel replacements in peripheral and coronary artery bypass. The ideal solution would therefore be to generate autologous SD blood vessels for use in these patients.

Approach

Autologous stem cells are isolated and eventually expanded in number. The non-differentiated stem cells are then cultured in 3D-Cell Culture on a decellularized- or nanofiber based vessel scaffold using a biaxial 3D-bioreactor. De-cellularized tissue with preserved extracellular matrix molecules have the advantage that it both directs the stem cells into the required cell lineages, but also provides the appropriate 3D-scaffold. The optimal synthetic scaffold simulating native extracellular matrix still remains to be developed. The recellularized  ”autologous” artery with no immunomodulary effect is then used in peripheral and coronary artery bypass to reperfuse the ischemic tissue.

Research Interest

Overall, our research lab focuses on understanding basics in fundamental biology in stem cells, tissue development and regeneration. In specific, we work on three different pipelines namely, 1) basic and clinical studies directed at understanding the ability of cardiac and fat stem cells to engraft into and regenerate different damaged tissues, 2) Unraveling the role of specific molecules in cardiac and fat stem cells during organ development and disease, and 3) mapping the signaling pathways of these specific molecules to understand their physiological and pathophysiological functions. This entails manipulation with their cellular levels and activity with the aim of developing diagnostic or intervention products to be used in treatment of different diseases. Furthermore, we are applying stem cells in several clinical settings evaluating the use of stem cell therapy of multiple diseases for future regenerative medicine.



Figure 1 Schematic representation of the overall project: Treating patients with ischemic cardiovascular disease using bioengineered SD blood vessel grafts.

(1) Decellularized blood vessels (DcV) or Nanofiber (NF) scaffold is prepared and stored until use. (2) Isolated autologous stem cells or whole blood (WBs), is then (3) cultured on the scaffold in a 3D-Bioreactor (TisXell Regeneration System). (4) Finally, bioengineered SD blood vessels are used to reperfuse the ischemic site in the patient with a subsequent recovery of the patient.

Available positions and Contacts

We always seek ambitious students (within medical or natural sciences) with a large degree of curiosity on nature’s biology. For questions, contact Ditte C. Andersen (dandersen@health.sdu.dk; +45 60113975) or Charlotte H. Jensen (charken@health.sdu.dk; +4523315275).

Research group

Ditte Caroline Andersen

Group leader
CV  |  Publications


  + 45 11 22 33 44
Dandersen@health.sdu.dk

Charlotte Harken Jensen

Associate professor
CV  |  Publications


  + 45 11 22 33 44
Charken@health.sdu.dk

Søren Paludan Sheikh

Professor
CV  |  Publications


+ 45 21 38 04 10
Soeren.sheikh@rsyd.dk

Key project members

  • Chief Consultant Lars Peter Riber; Department of Cardiothoracic and Vascular Surgery T/OUH.
  • Professor of Vascular Surgery, dr.med (DMSci.), Ph.D. Jes S. Lindholt; Department of Cardiothoracic and Vascular Surgery T/OUH.
  • Researcher Louise Katrine Kjær Weile Department of Gynaecology and Obstetrics/OUH.
  • Researcher Sussi B. Mortensen Department of Clinical Immunology/OUH.
  • Professor dr.med. Jens Ahm Sørensen; Department of Plastic Surgery/OUH.
  • PhD student Navid Toyserkani; Department of Plastic Surgery/OUH.

Lab page »

Selected publications

  1. Andersen DC, Ganesalingam S, Jensen CH, Sheikh SP: Do neonatal mouse hearts regenerate following heart apex resection? Stem cell reports (In Press) Expected April 3rd, 2014.
  1. Andersen DC, Laborda J, Baladron V, Kassem M, Sheikh S, Jensen CH. Dual role of Delta-like 1 homolog (Dlk1) in skeletal muscle development and adult muscle regeneration. ”. Development, 2013. 140:3743-3753.
  1. Aagaard KS, Ganesanlingam S, Jensen CH, Sheikh S, Andersen DC.Poor engraftment potential of epicardial progenitors upon intramyocardial transplantation into the neonatal mouse heart.” International Journal of Cardiology, 2013. 168:4360-4362.
  1. Nossent AY, Eskildsen TV, Andersen LB, Bie P, Brønnum H, Schneider M, Andersen DC, Welten SMJ, Jeppesen PL, Hamming JF, Hansen JL, Quax PH, Sheikh SP. “ The 14q32 MicroRNA-487b Targets the Anti-Apoptotic Insulin Receptor Substrate 1 in Hypertension Induced Remodeling of the Aorta”. Annals of Surgery, 2013. 258-743-753.
  1. Mortensen SB, Jensen CH, Schneider M, Laborda J, Sheikh S, Andersen DC. Membrane tethered Delta-like 1 homolog (Dlk1) restricts adipose tissue size by inhibiting preadipocyte proliferation. Diabetes. 2012. 61:2814-2822.

Funding