52 Effects of aging on stem cell function and ectopic fat accumulation in the musculoskeletal system

Background

The musculoskeletal system enables body movement and its deterioration is a crucial aspect of age-related functional decline. In bone tissue, beyond supporting hematopoiesis, MSCs differentiate into osteochondrogenic progenitor cells to form osteocytes and chondrocytes, or into adipogenic progenitor cells to ultimately become adipocytes. In the muscle, MSCs undergo adipogenic lineage commitment for healthy adipocyte turnover, but also secrete signals to support satellite cells which replenish the myofibrocyte pool. Thus, MSCs regulate cellular regeneration of osseous, cartilage, haematopoietic, and adipose tissue in bones, as well as adipose tissue and myofibres in the muscle. During aging, an accumulation of fat cells in the bone marrow cause a pathogenic expansion of ectopic bone marrow adipose tissue, which contributes to the development of osteoporosis and weakening of bones. Muscle-resident MSCs are prone to cause fatty infiltration and myofibre pathogenesis. These shifts in cell populations cause loss of osteocyte progenitors leading to osteoporosis in the bone, whereas in the muscle they impair regeneration thereby promoting the onset of sarcopenia.

Materials und Methods

Here we perform single-cell RNA sequencing analysis, and characterize the cell type-specific transcript regulation in stem cells from murine bone samples after certain nutritional interventions and as a function of age, and murine muscle tissue samples after aging or muscle injury to analyse the transcriptional changes responsible for the transition of healthy fibroadipogenic progenitors to a pathological state. In both tissues, we apply novel bioinformatics tools to model predictions of cell differentiation and transcription states in defined cell types.

Results

We identify novel transcriptional and regulatory mechanisms that shape the niche of both bone- and muscle-resident MSCs. We characterize gene expression patterns that contribute to the transition from a healthy to a pathological lineage commitment in both settings, and identify new processes that modulate this transition.

Conclusion

In summary, we were able to observe critical changes in the bone marrow and muscle niches, which give clues to mechanisms of healthy bone and muscle regeneration as a function of age and diet. Targeting these processes might improve musculoskeletal health and prevent the negative effects of pathological cell lineage determination.

Publication History

Article published online:
24 September 2021