Multipotent Mesenchymal Stem Cell Treatment for Discogenic Low back Pain

It is well documented that low back pain is a common and debilitating condition. Medical expenses and lost wages exceed $100-200 billion annually in the United States alone. The intervertebral disc has been identified as the single most common pain generator for low back pain. 

The interest in emerging bioregenerative therapies has increased over the years to treat painful pathologic discs as current interventional and surgical options appear to provide inconsistent painful relief and offer no restorative potential. 

Normal Disc Anatomy

A normal disc is composed of the nucleus pulposus (NP), annulus fibrosus (AF) and the vertebral endplate. The NP contains randomly organized collagen and elastin fibers embedded in a highly hydrated gel-like matrix rich in proteoglycan (PG), which is synthesized by chondrocyte-like intervertebral disc (IVD) cells. 

The nuclear matrix is about 70-90% water. The NP plays an important role in spine flexibility and axial load distribution. The surrounding annulus (AF) is composed of parallel collagen fibers and its cells are similar to fibroblasts. The annulus provides tensile strength and works in conjunction with the nucleus to absorb shock. 

The last component, the cartilaginous vertebral endplate, is composed of both hyaline and fibrocartilage and is intimately involved in connecting and anchoring the disc to the vertebral body. 

What Causes Disc Degeneration? 

The IVD is a dynamic structure. Its microenvironment relies on a harmonious balance between anabolic (growth factors) and catabolic (inflammatory cytokines) factors important for normal disc cell turnover. 

Due to the relatively avascular disc characteristics a harsh microenvironment is created, with acidic pH, low oxygen tension and low nutrients for IVD cells, which also contributes to the poor natural regenerative capacities of the IVD when pathologic changes happen. 

How Is It Diagnosed? 

Clinical history and exam can suggest the disease, but the diagnosis is made by advanced imaging like MRI, which is the best noninvasive imaging modality to define disc pathology. 

MRI can also be utilized to grade the severity of disc degeneration, detect vertebral endplate/subchondral bone pathology, and identify the presence of disc herniation.

Current Treatments

If conservative treatment modalities (medications, physical therapy, back braces) fail, trained clinicians have traditionally used interventional techniques to aid in providing pain relief. 

Current treatment options are considered suboptimal in the treatment of discogenic pain because they fail to accomplish the entirety of objectives for disc pathology treatments, which are: 

• Decline and/or resolution of pain (with functional improvement). 
• Slowing and/or reversal of the catabolic metabolism (associated with degradation).
• Partial or complete restoration of disc tissue. 

Another treatment option are epidural injections, which normally provides pain relief for a short period of time. Spinal surgery is considered only if there is nerve damage or the back pain does not heal after a long time. 

Multipotent Mesenchymal Stem Cell Treatment 

The use of percutaneously delivered Multipotent Mesenchymal Stem cell (MSC) treatment has recently gained attention for its potential to revolutionize the treatment of discogenic LBP and associated disc degeneration. 

MSC provides the necessary cellular support for regeneration and current research suggests that these treatments may have the ability to uniquely accomplish the three stated objectives for treating disc pathology. 

MSCs have the ability to differentiate into osteoblasts, adipocytes and chondroblasts under in vitro conditions and studies have revealed that they can act locally to accomplish many functions. MSCs are known for their self-renewal capacity and chemotactic facilitation of cellular activity. Also, they can modulate the immune response with their antiinflammatory effect. 

Sources of MSCs

The most studied types of MSCs that are currently being used are those derived from bone marrow, adipose tissue and umbilical cord tissue. 

• Human umbilical cord tissue derived MSCs (HUC-MSCs): are easily collected from cord tissue and have potential allogeneic application. They are perhaps the best source of cells for expansion. They could be well suited for allogeneic use because they demonstrate low-immunogenicity.
  
• Bone marrow MSCs (BM-MSCs): they can stimulate native disc cells and differentiate into IVD-NP cells. To obtain these cells a bone marrow aspirate needs to be collected (commonly from the posterior iliac crest). BM-MSCs have been injected intradiscally in both animal and human models with promising results.
  
• Adipose derived MSCs (ADSCs): can be easily collected from fatty tissue. Some consider adipose a superior source because of the relatively higher concentrations of MSCs within the tissue.

Evidence for MSCs Therapy for Discogenic LBP and Disc Degeneration

Disc microenvironment is important for growth and viability of native IVD cells as well as injected MSCs. In vitro studies combining MSC and IVD cells have demonstrated that they promote an anabolic microenvironment. 

A study by Lui et al. showed evidence that BM-MSCs could secrete anti-inflammatory TGF-b and IL-10. The combination of MSCs and IVD-NP cells has resulted in IVD-NP cell proliferation and disc tissue regeneration.

Various in vivo animal models have demonstrated similar results and regenerative effects. Because there are clear mechanical differences on the IVD with a quadrupedal animal, human in vivo studies are needed to confirm reduction or elimination of discogenic pain. 

A study involving 10 patients with discogenic LBP and degenerative disc disease (>50% disc height loss) by Orozco et al. used autologous BM-MSCs demonstrated safety and feasibility in a percutaneous approach. The patients underwent a single injection after failing 6 months of conservative treatment. The researchers reported statistically significant improvements in pain and disability after 3 months, with results persisting after a year. They also saw water content improvement at the disc level. 

Conclusions 

Evidence suggests that MSCs may fulfill the final major objective of reversing disc tissue loss. Currently, symptomatic patients have been encouraged to pursue conservative therapies, reserving interventional injections for nonresponders and spine surgery for severe cases. 

This dogma applies to multiple diseases, but could change if more and larger clinical studies demonstrate consistently safe and effective, MSC-based therapy could lead towards a more aggressive nonsurgical care for patients with discogenic LBP. 

Sources: 

Zeckser J, Wolff M, Tucker J, Goodwin J. Multipotent Mesenchymal Stem Cell Treatment for Discogenic Low Back Pain and Disc Degeneration. Stem Cells Int. 2016;2016:3908389. doi:10.1155/2016/3908389.

https://medlineplus.gov/ency/article/007422.htm

Image from: https://allpria.com/conditions-we-treat/back-pain/degenerative-disc-disease/