Spinal disc degenerative disease has become an increasingly more important medical issue with our aging population. Greater than 20% of the physician visits for people older than 65 years are related to low back pain, the majority of which is due to spinal disc degenerative disease and its many serious sequelaes.1,2 The micro-instability caused by the disc degeneration is associated with the development of spinal stenosis, spondylolisthesis and adult deformity, leading to severe pain and disability. Our older population demands a healthy lifestyle and the cost for the treatments of the widely prevalent spinal degenerative diseases has been one of the major reasons for the society’s soaring medical cost.3 Finding an effective intervention that delays the disc degeneration process potentially has enormous health and economical implications. However, little is known about the pathogenesis of disc degeneration process beyond the observation that intervertebral discs gradually lose water content and extracellular matrix with aging.
Recently, using a colony-forming assay with human and mouse nucleus pulposus cells, a Japanese group (Sakai et al) identified a multipotent Tie2 positive and disialoganglioside 2 (GD2) positive cell population which forms spheroid colonies in tissue culture and expresses type II collagen and aggrecan (Figure 1).4 After injecting the Tie2+GD2+ nucleus pulposus cells transduced with enhanced green fluorescent protein (EGFP) into the intervertebral disc in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice tail, EGFP+ cells were found to be surviving for at least 12 weeks in the disc space, integrated into the host nucleus pulposus and expressing type II collagen in vivo (Figure 2).
More interestingly, the authors noticed the correlation between the gradual disappearing of the Tie2+ nucleus pulposus cells with aging and disc degeneration in surgically removed human disc samples (Figure 3). The proportion of the Tie2+ cells in the nucleus pulpusus cells and their colony forming capacity decreases with aging and the extent of disc degeneration, suggesting the role of Tie2+ progenitor cells in rejuvenating the intervertebral discs. The gradual loss of the Tie2+ progenitor cells with aging may be the cause of age-related disc degeneration.
How is the survival the Tie2+ progenitor cells in the nucleus pulposus regulated? The authors found that angiopoietin-1, a ligand of Tie2, co-expresses with Tie2+ progenitor cells. Blocking the interaction between Tie2 and angiopoietin-1 led to increased apoptosis in the nucleus pulposus cells while co-culturing of Tie2+ cells with soluble angiopoietin-1 promoted Tie2+ cells proliferation and colony-forming capacity. Angiopoietin-1 is widely involved in the regulation of endothelial homeostasis and vascular proliferation. The finding of its involvement in the survival of nucleus pulposus progenitor cells in this traditionally avascular environment is intriguing.
Despite the wide prevalence of intervertebral disc degeneration and its deep impact on the health status of our increasingly aging population, little is known about its pathogenesis. The identification of the progenitor cell group in the nucleus pulposus and its aging related loss may hold the answer to this process. With the rapid advancement in stem cell technology, this finding may have opened an exciting door for the finding of therapeutic strategies that could one day delay or reverse spinal disc degeneration process and decrease the pain and suffering of our aging population from degenerative spinal disorders.
1. Hart LG, Deyo RA, Cherkin DC. Physician office visits for low back pain. Frequency, clinical evaluation, and treatment patterns from a U.S. national survey. Spine (Phila Pa 1976). 1995;20(1):11–19.
2. Deyo RA, Mirza SK, Martin BI, Kreuter W, Goodman DC, Jarvik JG. Trends, major medical complications, and charges associated with surgery for lumbar spinal stenosis in older adults. JAMA. 2010;303(13):1259–1265.
3. Martin BI, Deyo RA, Mirza SK, et al.. Expenditures and health status among adults with back and neck problems. JAMA. 2008;299(6):656–664.
4. Sakai D, Nakamura Y, Nakai T, et al.. Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc. Nat Commun. 2012;3:1264.