Research Interests

Aging has dramatic and far-reaching effects on most organ functions, as it negatively impacts on strength, healing, bone density, and many more. As it is well perceived that stem cells are the single most important starting point for regenerative processes, the fitness of this specialized cell type is considered pivot, not only in the developing and growing organism, but seemingly decisive later during adult life. Stemness and multipotentiality of MSC undergo age-associated variations. In this respect, the basic properties of MSC have been acknowledged also for putative clinical applications, both as an emerging field on its own, as well as part of the so-called regenerative medicine.

My research group addresses two fundamental questions in stem cell biogerontology:  

(1) What age-associated mechanisms impinge on MSC stemness and integrity
(2) which typical cellular interactions in the aging stem cell’s niche impact on their basic stem cell properties.

Hence our experimental research is focusing on those cell-intrinsic and extrinsic specifications, which occur in vivo and decisively influence MSC functionality either resulting in the decline in regenerative potential, or as a direct consequence, promoting age-associated diseases. In order to gain the broadest possible insight into dynamic changes, in most projects, genomic analytical tools and approaches have been applied in the recent years. In particular in a recently initiated project we now attempted to determine the translational efficiency of MSC we could successfully employ a combination of biochemical fractionation of differentially polysome-loaded mRNA and micro-array analytics thus giving insight on relative protein synthesis of the cell. We are confident that with this enomic approach we can efficiently bridge the gap to proteomics.

Working along these lines, a novel concept of stem cell fitness is currently being specified by identifying autocrine factors and MSC-intrinsic molecular networks, which entail and account for robust proliferative capacity or stemness, together with enhanced systemic MSC endurance life.

Previous findings by GL’s research group

Major issues in the aforementioned context are to investigate the changes that occur in MSC with advancing age, and more than that whether these changes are causative for age-related deviations. To analytically approach this question, we study primary MSC from bone of differently aged, yet systemically healthy human donors who undergo plastic surgery at the Craniomaxillofacioal Surgery Unit of the University Clincis Innsbruck.

We could demonstrate that MSC numbers barely decline with age. In contrast to that, long-term in vitro proliferation potential of explanted MSC was significantly diminished in cells derived from elderly donors.

Inflamm-aging: with advancing donor age, MSC actually raise the expression level of vascular cell adhesion molecule 1, also called CD106, which is also greatly boosted in response to pro-inflammatory stimuli. Increasing doses of interferon gamma exerted no immediate influence on the proliferative potential of MSC, but distinctly affected their respective commitment to either differentiate towards the adipogenic or osteogenic lineage. Moderately elevated levels of inflammatory stimuli support osteoblastogenesis and are thus instructive for healing processes, while excessive or chronic inflammatory insults promote adipogenic differentiation and adipose upgrowth.

MSC fitness: we also recognized large inter-individual variation between MSC from different donors. Hence, instead of taking chronological donor age as a measure for MSC quality, we next defined age-matched pairs of primary MSC with largely differing proliferation potential in order to stipulate changes related to biological age. Working along this line, many genes were found to be differentially expressed with high statistical significance. Amongst others, one gene that encodes for a secreted short peptide which can act systemically as a hormone with described functions on nerve and immune cells as well as in stress perception was further functionally tested with regard to enhancement of MSC stemness. Exogenous supplementation of the hormone to MSC cultures enhanced self-renewal of MSC by strongly activating the pluripotency transcription factors SOX2 and nanog. Also members of the E2F family were found differentially regulated factors, which we consider responsible for the increased proliferative capacity observed after treatment with the peptide, as well as in a fit MSC population. Conclusively, MSC that for whatever reasons secrete more of the hormone are capable of maintaining stemness by autocrine cues. More than that, wholesomely fit MSC serve as potent systemic hubs for modulating neuronal and immunological activity.

Conclusion: The outlined results actually suggest that stem cells are imprinted in a way to efficiently compensate for potential systemic failures resulting from major changes in allostatic load. Provided that, the research group is now seeking means and ways of better understanding these highly complex interconnected relationships by applying integrating methods at a systemic level.

Cooperations and Funding: Increased longevity should be celebrated and not seen as a burden, but improved healthy ageing is an essential prerequisite. Age-associated diseases include osteoporosis and osteopenia, its precursor; impaired immunity; poor healing and general frailty. These and associated conditions are difficult to manage, significantly impair quality of life and there are many non-responders to conventional medical therapy where such exists. It is in the interests of both individuals and broader society that healthy independent living be maintained as long as possible. Improved biologic understanding and, importantly, the transfer of this understanding into common knwoledge is essential to enable people to live fulfilled and independent lives for longer resulting in reduced social and economic costs. Therefore the research group coordinates or entertains strong multidisciplinary translational research collaborations with partners having fundamental expertise in tissue engineering and regenerative medicine, complementing engineering expertise in microfluidics, -omics and biosensor technology.

The research group with its autonomous research activities further actively lobbied into strong alliances with cooperation partners at the Medical University Innsbruck and its Clinics and other academic and industry partners. These scientifically most fruitful collaborations have not only supported the department’s efforts in its prime research enterprise, which are dedicated to study MSC aging, but also complementing the endeavor of the clinical collaborators to implement novel technologies based on stem cell biology and regenerative medicine into a clinical setting. Novel concepts have been successfully seeded into extended cooperative network programs at a national and European level either being initiated or joined by the research group, such as the project “VASCUBone” – funded under EU FP7, the project “Smart Implants” - funded by the “Tiroler Zukunftsstiftung”, the project “DIALIFE” – funded in the context of Laura Bassi Center of Excellence by the Austrian Research Promotion Agency and the project “The role of MSC in the therapy of osteoarthritis” funded by the Austrian Science Fund (FWF). Research to be conducted in the context of these newly granted projects has commenced early 2010.

Nach oben scrollen