Should Degenerated Intervertebral Discs of Patients with Modic Type 1 Changes Be Treated with Mesenchymal Stem Cells?

Abstract

Low back pain (LBP) has been among the leading causes of disability for the past 30 years. This highlights the need for improvement in LBP management. Many clinical trials focus on developing treatments against degenerative disc disease (DDD). The multifactorial etiology of DDD and associated risk factors lead to a heterogeneous patient population. It comes as no surprise that the outcomes of clinical trials on intradiscal mesenchymal stem cell (MSC) injections for patients with DDD are inconsistent. Intradiscal MSC injections have demonstrated substantial pain relief and significant disability-related improvements, yet they have failed to regenerate the intervertebral disc (IVD). Increasing evidence suggests that the positive outcomes in clinical trials might be attributed to the immunomodulatory potential of MSCs rather than to their regenerative properties. Therefore, patient stratification for inflammatory DDD phenotypes may (i) better serve the mechanisms of action of MSCs and (ii) increase the treatment effect. Modic type 1 changes-pathologic inflammatory, fibrotic changes in the vertebral bone marrow-are frequently observed adjacent to degenerated IVDs in chronic LBP patients and represent a clinically distinct subpopulation of patients with DDD. This review discusses whether degenerated IVDs of patients with Modic type 1 changes should be treated with an intradiscal MSC injection.

Keywords: Modic change; immunomodulation; intervertebral disc; mesenchymal stem cell; regeneration; stem cell therapy.

Figure 2

Schematic illustration of possible causes of pain and inflammation in ‘MC discs’, comparing a ‘healthy disc’ (on the left side) to a ‘Modic disc’ (on the right side). Note that the central role is given to the CEP: CEP damage possibly enables inflammation in the adjacent vertebrae, triggering a cross-talk to inflammatory cells. Ingrowth of nerve endings into the IVD might be responsible for pain development. Increased osteoclast activity might be responsible for the inflammatory trabecular bone resorption observed in MC1 [14,15,17]. MSCs in the bone marrow adjacent to ‘MC1 discs’ have a pro-fibrotic phenotype [46], possibly due to the pro-fibrotic and pro-inflammatory cross-talk with the ‘MC1 disc’.

Figure 1

Sketches of intensity changes when scanning vertebral columns of human patients and classification of the three distinguishable MC according to T1- and T2-weighted sequences on MRI [15]. MC are classified into (A) MC type I, hypointense in T1 and hyperintense in T2, (B) MC type 2, hyperintense in T1 and T2, and (C) MC type 3, hypointense in T1 and T2.

Figure 3

Schematic illustration of the possible multimodal mode of action of intradiscally injected MSCs in MC1. MSCs might regenerate the ‘MC1 disc’, repair the CEP leakage, and suppress osteoclast activity, thereby improving the tolerance for mechanical load. Suppression of discal inflammation and sealing of the CEP leakage might disrupt the inflammatory ‘MC1 disc’/bone marrow cross-talk, thereby suppressing nerve ingrowth and discogenic pain. OCs = osteoclasts.