Nova spoznanja o lastnostih in vlogi mišičnih mezenhimskih stromalnih/ matičnih celic v primerjavi z istovrstnimi kostnimi celicami pri osteoporozi in osteoartrozi
New insights into characterization and role of muscle-derived mesenchymal stromal/ stem cells in comparison to their bone-derived counterparts in osteoporosis and osteoarthritis : doktorska disertacija

english
slovenian

doktorska dela

2020

Univerza v Ljubljani, Fakulteta za farmacijo
(Obvezni izvod spletne publikacije)

With aging, musculoskeletal disorders such as osteoarthritis (OA), osteoporosis (OP) and sarcopenia are gaining importance. Microscopic injuries occur throughout the life of bones and muscles, but in spite of this they continue to provide the body with the support needed for daily activities. Our current understanding is that the regenerative capacity of the skeletal muscle system can be attributed to mesenchymal stromal / stem cells (MSCs). MSCs can serve different tissues as a reservoir of progenitors that form functional cells such as osteoblasts, chondrocytes, myocytes, and others. However, with aging and disorders of the musculoskeletal system, this regenerative ability of MSCs is lost or redirected to the production of other non-functional cell types, such as adipocytes and fibroblasts. There is increasing evidence that tissue specific MSCs have different properties. However, it is not clear how these traits are affected by aging and disease. Studies that directly compare MSCs from different tissues of the skeletal muscle system in the same patient are rare, and the impact of skeletal muscle diseases such as OA, OP and sarcopenia on MSCs is poorly understood. Thus, the purpose of this doctoral thesis was to evaluate MSCs isolated from the skeletal muscle of the gluteus medius and spongy bones of the femoral head of patients with OA and OP at the level of their phenotype and the ability to proliferate and differentiate in vitro in order to detect functional differences between them that could explain pathological changes in musculoskeletal diseases and discover new targets for their more effective treatment and diagnosis. In this doctoral thesis, we were the first to thoroughly evaluate the properties of muscle derived MSCs in patients with primary osteoarthritis and osteoporosis. We have shown that growth rates and doubling times of muscle and bone MSCs in vitro are comparable and independent of the type of disease. The ability to form colonies of cultured muscular MSCs (clonigenicity) was higher in OA and OP compared to bone MSCs. We have shown that in patients with OP, the adipogenic potential of muscle MSCs is greatly increased, which could indicate a role for these cells in the formation of fatty infiltrates. We were also the first to show an association between a subset of MSCs expressing the CD271 gene and the degree of adipogenicity of muscle MSCs. In the future this surface marker could possibly represent a new therapeutic target or a new indicator in the diagnosis of musculoskeletal diseases. We also confirmed the presence of Gremlin1-expressing MSCs in skeletal muscle and showed its association with increased in vitro clonigenicity in OA patients. In addition, we further confirmed the already known 4 association between the CD56-positive subset of muscle stem cells and their myogenic potential. The results of our research have shown that skeletal muscle is an appropriate and effective source of MSCs suitable for use in regenerative medicine, including in elderly patients with chronic musculoskeletal disorders.

12.05.2023