Cellular Approaches to Disc Regeneration

Two cellular strategies using different candidate cell types have been identified as potentially useful in regenerating discs. The first technique uses differentiated chondrocytes and disc cells from normal discs; the second uses mesenchymal stem cells (MSCs). These stem cells, available from a number of autologous sources, are less mature and, therefore, have the potential to divide and produce larger quantities of disc material. (Mature disc cells do not readily divide and are available only from healthy discs.)

Alterations in the culture conditions of MSCs lead to the expression of different phenotypes. If cultured on monolayer, they tend to develop along fibroblast pathways. Three-dimensional culture matrices allow development of disc-like cells (2). As the disc is avascular in its normal state, culture with low oxygen tension and a slightly acidic environment tends to increase the production of disc cells (3).

Growth factors also are important in the production of disc cells in culture. For example, BMP-7 has been shown to increase output of matrix proteins (4). The timing and concentration of growth factor application also can affect cell division and matrix production. The exact relationships and interaction of these factors remains undefined.

Studies of cellular strategies for disc regeneration in animal models of disc degeneration have been done. Gruber has shown that culture-expanded autologous nuclear cells can be transplanted and express extracellular matrix proteins (5). In a canine model, Ganey showed that animals injected with expanded disc cells had more normal disc height and structure (6).

Using MSCs cultured in a threedimensional matrix in a rabbit model, Sakai showed proliferation and increased matrix production (7). In a similar model, Sato showed that discs injected with MSCs showed less signs of degeneration (8).

In the one clinical trial conducted to date using autologous disc cells, cells were harvested from an early-stage degenerate disc, expanded in mono-layer culture, and then injected. Short-term follow-up showed increased disc height, but there has been no report of clinically validated outcome measures, and data have not been published in a peerreviewed journal (9).

Cellular strategies for disc regeneration seem to have some potential. Cell numbers and matrix production can be increased. It remains to be seen, however, whether these changes will alter the clinical course of disc degeneration. Early human clinical trials show results similar to those of animal studies. The longevity of these transplanted cells also has not been determined. Although these strategies hold promise, it will be many years before they reach common clinical practice. Ultimately, the optimal approach most likely will involve a combination of cellular and molecular strategies.

General References
1. Buckwalter JA. Aging and degeneration of the human intervertebral disc. Spine. 1995;21:2820-2825.

2. Gruber HE, Leslie K, Ingram J, Norton HJ, Hanley EN. Cell-based tissue engineering for the intervertebral disc: in vitro studies of human disc cell gene expression and matrix production within selected cell carriers. Spine J. 2004;4:44-55.

3. Risbud MV, Alpert TJ, Guttapalli A, et al. Differentiation of mesenchymal stem cells towards a nucleus pulposis-like phenotype in vitro: implications for cellbased transplantation therapy. Spine. 2004;29:2627-2632.

4. Takagami K, Thonar EJ, An HS, et al. Osteogenic protein 1 enhances matrix replenishment by intervertebral disc cells previously exposed to interleukin 1. Spine. 2002;27:1318-1325.

5. Gruber HE, Gordon B, Williams C, et al. Autologous interverebral disc cell implantation a model using Psammomys obeseus, the sand rat. Spine. 2002;27:1318-1325.

6. Ganey T, Libera J, Moore V, et al. Disc chondrocyte transplantation in a canine model; a treatment for degenerated or damaged intervertebral disc. Spine. 2003;28:2609-2620.

7. Sakai D, Mochida J, Yamamoto Y, et al. Transplantation of mesenchymal stemm cells embedded in atelocollagen gel to the intervertebral disc: a potential therapeutic model for disc degeneration. Biomaterials. 2003;24:3531-3541.

8. Sato M, Asazuma T, Ishihara M, et al. An experimental study of the regeneration of the intervertebral disc with an allograft of cultured annulus fibrosis cells using a tissue engineering method. Spine. 2003;28:548-553.

9. Co.Don: Autologous Chondrocyte disc transplantation. www.codon.de. Last accessed Dec. 20, 2004.