Gunter Lepperdinger
University Salzburg
Austria
Title: Triggering osteocytogenesis in vitro and in vivo
Biography
Biography: Gunter Lepperdinger
Abstract
Mesenchymal stromal cells (MSC) can be reliably isolated from human connective tissues. Naïve MSC can be culture-expanded and induced to form osteoblasts in a standardized manner. Further differentiation to gain osteocytes is however hard to achieve; also knowledge concerning the molecular mechanisms which specifically trigger and convey osteocyte differentiation is scarce. Through a serendipitous observation while investigating the role of hyaluronan in MSC biology, we were able to unveil molecular mechanisms of osteocytogenesis. These involve specific stress response mechanisms regarding detoxification by means of glucuronidation, upregulation of O-glycosylation which grossly changes the cellular phospho-proteome, induction of stress granule formation and concomitant mRNA-binding thereby yielding differential regulation of translation of osteogenic transcription factors and the formation of poly-ADP–ribose (PAR) in the cytoplasm otherwise known to coordinate the nuclear DNA repair machinery. We could further show in 3D-mesenspheres that provoking this particular stress response pathway in the presence of osteogenic inducers promotes the calcification of MSC-derived microorganoids resulting in the formation of trabecular-like hard tissue structure bearing osteoblastic linings which engulf marrow-like stroma. These observations could be further corroborated in histological sections of human bone in particular showing the presence of stress granule and PAR deposition in osteocytes residing in compact bone. We could further show accelerated healing of a bone defect model in rat calvaria by provoking this stress response pathway.