Therapeutic potential of adipose-derived stromal cells for the treatment of senile osteoporosis

Summary Impaired osteogenic differentiation of resident bone marrow stromal cells (BMSCs) of aged patients with low turnover osteoporosis is considered to be one of the major contributing factors in the development of structural and mechanical deficiencies associated with osteoporotic bone. As such, therapies designed to counteract these effects are currently being pursued with an aim to restoring the stem cell niche and enhancing bone quality. In the current thesis, evidence is provided which supports the use of autologous adipose-derived stromal cells (ASCs) as a means by which to combat age-related bone loss. Initial studies were undertaken to compare the differentiation potential of ASCs from osteoporotic SAMP6 and non-osteoporotic SAMR1 mice in 2D in vitro culture systems. Their ability to differentiate towards osteoblast and adipocyte cell lineages was evaluated by histological, biochemical and molecular techniques. In contrast to BMSCs, the differentiation potential of ASCs was found to be comparable between both strains. Further in vitro studies were performed to assess the osteogenic potential of SAMP6-derived ASCs cultured under 3D conditions using long-term silk fibroin scaffold cultures and short-term scaffold free microtissue spheroid (ASC-MT) cultures. In both cases, ASCs underwent efficient osteogenesis resulting in mineralized tissue formation. In the final study, ASCs and ASC-MT were evaluated for their ability to enhance trabecular bone quality following a single intratibial injection in SAMP6 mice using micro-CT, histological and molecular based analyses. Both ASCs and ASC-MT could be identified within treated bones after 42 days and moreover, resulted in significant improvements in several parameters of trabecular bone quality. Furthermore, human ASCs harvested from osteoporotic patients were also demonstrated as having a positive influence on the osteogenic differentiation potential of dysfunctional osteoporotic patient-derived BMSCs in vitro. I