Cellular Aging – Challenge for Intervertebral Disc Regenerative Therapy

Degenerative changes of the intervertebral disc (IVD) are agreed to be major cause of low back pain (LBP). LBP – with lifetime prevalence of 70% [1] – is the most prevalent health problem of the industrialized countries nowadays. More than this, a population survey in Switzerland revealed that 47% of women and 39% of men had back problems in the preceding 4 weeks – again representing the highest prevalence of all the reported health problems [2]. Back pain frequency, treatment and costs are the object to no less than 49 systematic reviews [3] and put tremendous pressure on worldwide healthcare and social systems; everything suggests that the current treatment modalities are far from optimal.

Mesenchymal stem cells (MSCs) are expected to be fundamental players in future cell-based therapies of the musculoskeletal system because of their high proliferative ability, multi-lineage potential and anti-inflammatory properties. However, the different regenerative qualities of the cells can be a problem for translating promising research into human clinical practice. Autologous transplantations have the “elephant in the room” problem of wide donor variability, reflected by variability in MSCs quality and characteristics at different stages of manipulation, leading to uncertain outcomes in the use of these cells. Significantly, time spent in culture before the loss of required differentiation potential is different and reflects patient variability, which is a problem for cell expansion. We have previously used different methods to assay cell senescence and differentiation potential but they are time-consuming with experiments lasting between one week and a month [4]. The functional test results showed that osteogenic and chondrogenic differentiation potential decreased upon replicative senescence, whereas the predisposition for adipogenic differentiation increased in higher passages. While several other studies show that differentiation potential drops with the ongoing in vitro culturing of MSCs, the practical implications and the reliability of the different senescence criteria are less clear. Here we will discuss a new approach to use the cell motility as a potential stem cell marker for the fitness of the cells [5]. We also discuss why it does not make sense to put ‘fit cells’ in ‘degenerative environment’ and how physical and rehabilitation medicine can play the most important role in the success of future cell therapies.

Fig. 1: Time-laps microscopy of tracking the movement (colour lines) of individual stem cells over 24 hours reveals remarkable differences in cell motility between donor A and donor B. (Color figure available online only).

References:

[1] Becker, A. et al. Low back pain in primary care: costs of care and prediction of future health care utilization. Spine (Phila Pa 1976) 35, 1714 – 1720 (2010).

[2] Wieser, S. et al. Cost of low back pain in Switzerland in 2005. Eur J Health Econ (2010).

[3] McIntosh, G. & Hall, H. Low back pain (acute). Clin Evid (Online) 2011 (2011).

[4] Bertolo, A. et al. An in vitro expansion score for tissue-engineering applications with human bone marrow-derived mesenchymal stem cells. Journal of tissue engineering and regenerative medicine (2013).

[5] Bertolo, A. et al. In vitro cell motility as a potential mesenchymal stem cell marker for multipotency. Stem cells translational medicine 4, 84 – 90 (2015).