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Start of funding 01.01.2010
Establishment of an association between age of subcutaneous mesenchymal stem cells and inefficient pro-angiogenic activity
Prof. Dr. Günther Machens
Technische Universität München
Dr. Jan A. Nolta
University of California, Davis
Stem Cell Program
During wound healing, the regeneration potential of tissues such as skin is well known to decay with age, representing a major clinical problem. Among others, the damaged tissue relies on a proper vascularisation to re-establish functional recovery. Recent reports establish mesenchymal stem cells (MSC) as key players during the revascularization process, due to their potential to release pro-angiogenic factors and probably, since MSC correspond to pericytes, supporting structurally new blood vessel formation. MSC are indeed being tested in clinical trials to treat low-vascularized tissues such as critical limb ischemias or ischemic heart disease.
Our aim is to identify putative alterations in skin-derived MSC during aging, which could play a critical role in the wound healing process. In order to test this, a bank of human subcutaneous MSC will be established in Dr Machens lab from donors at highly varying ages. In Nolta’s lab, these cells will be characterized in terms of their proliferation and angiogenic potential. Specifically, MSC will be evaluated ex vivo for the potential to form fibroblast colony forming units (CFU-F), to proliferate, typical immune phenotype and release of angiogenic factors such as SDF-1a, bFGF and VEGF at RNA and protein levels. In order to test their angiogenic potential in vivo, two well established methods will be applied. First, in Dr Nolta’s lab, a unilateral hind limb ischemia in NODSCIDbeta2null mice by excision of the femoral artery and intravenous transplantation of MSC, allows a periodic measurement of blood flow restoration by Doppler imaging. Second, in Dr Machens lab a full skin defect model in nude mice, with localized implantation of MSC in a xenograft collagen-based scaffold will permit an accurate quantification of new blood vessel formation. This work will identify critical alterations in subcutaneous MSC associated with donor’s age that may explain the putative poor regenerative potential of the cells.