stem cell

Mesenchymal stem cell therapy: a viable non-surgical option in lower back pain treatment

Virginia Thornley, M.D., Neurologist, Epileptologist

June 9, 2018

Introduction

Back pain is one of the most common pain disorders encountered by neurologists, neurosurgeons, orthopedic surgeons and pain specialists in the out-patient setting. It is not uncommon for patients to go through an extensive list of medications, steroid injections, physical therapy and even surgery and still remain in unrelenting pain. There is a growing interest in alternative treatments especially with the opioid crisis looming and restriction of strong pain medications. This seeks to review scientific mechanisms behind the success in stem cell treatment. It recaps clinical data. Despite a scarcity of published huge randomized clinical trials, there is a growing and clamoring need for alternative treatments such as stem cell therapy for patients desperately trying to find alleviation from their pain. Trailblazing physicians are using this treatment option in real life practice with growing results.
Back pain is a very common disorder which is especially prevalent in the elderly after wear and tear of long-term activity in conjunction with the natural degenerative changes that come with the aging process. Normally the intervertebral disc complex can withstand compression and shear forces because of the proteoglycans that bind water molecules. This becomes lost with aging. In degenerative disc disease, there are pro-inflammatory molecules.

Pathogenesis of degenerative disc disease
Within the nucleus pulposus, there is no vascular supply except at the end neural plate, has no nerves and is prone to damage. The nucleus pulposus relies on glycolysis for effective disposal of waste products through the endplates. After decades, the nucleus pulposus no longer has notochordal features and is replaced by small chondrocyte like cells. There is replacement of the collagen type 1 and collagen type 2 loss eventually replaced with fibrocartilaginous material. Eventually with time, the endplates have calcification of the small pores where molecules diffuse (1).

 

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There are anabolic processes involved as well as catabolic processes including involvement of enzymes, inflammatory mediators, proteinases, aggrecanases. Examples include IL-1 and TNF-alpha. because the disc is avascular this creates an environement of poor regenerative responses with harsh conditions (3).

Some patients may have a genetic predisposition to have flawed extracellular matrix where degenerative disc disease may occur more severely than in other people. Cleavage of proteoglycan can occur with enzymes resulting in loss of height and less ability to reduce compressive and shearing forces. In addition, environmental factors including occupational activities, excessive physical activity impacting the spine may contribute towards degenerative disc disease (1).

Alternative treatment: stem cell therapy
In order to address these issues, various treatments have arisen to try to try to halt the cascade leading to degenerative disc disease. This includes implantation of biomolecules to reduce the catabolic process.

 

 

Stem cell research is gaining more traction as a viable alternative for treatment of this debilitating condition. One study looked at the potential of nucleus pulposus-like cells derived from mesenchymal cells in the rabbit model. From these cells, SOX9, ACAN, COL2, FOXF1, and KRT19 genes were expressed(2). Transplanted nucleus pulposus cells were integrated into the intervertebral disc complex. Improved water content, glycosaminoglycan, and cellularity within the complex was noted. There was a suggestion of biosynthesis with the gene expression of SOX9, ACAn, COL4 (2). This animal study demonstrates that there may be value in nucleus pulposus cells derived from mesenchymal cells may lead to clinical studies where stem cells can be used for back pain.

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Injection of mesenchymal stem cells
Injections of mesenchymal stems cells into the disc may reduce the clinical pain and restore disc tissue loss. It may be able to reduce the catabolic microenvirnment (3)

Clinical studies of stem cell use in humans
It appears that stems cells of mesenchymal type derived from adipose or the umbilicus may have the most promise (4).

In one small study of 10 patients, autologous bone marrow mesenchymal cells were were injected in the nucleosus pulposus and followed for a year. After 3 months, there was improvement of pain and disability of 85% of the maximum. After 12 months, there was still high water content within the nucleosus pulposus (5).

Stem cell effects were studied in 2 patients with back pain and leg numbness. Marrow fluid was obtained autologously from the ilium from each patient. Mesenchymal stem cells were cultured in autogenous serum. Fenestration was performed and collagen sponge was applied percutaneously to the affected intervertebral disc complex. After 2 years, the T2 signal was high showing increased disc content in the grafted discs. Clinical symptoms were ameliorated (6).

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Clinical trials
In an open label trial of 26 patients, using the VAS and Oswestbry disability scale, there was reduced pain after percutaneous injection of bone marrow cell concentrate showing autologous mesenchymal stem cells are a viable alternative treatment for back pain (7). They studied the patients through 12 months. Those who received >2000 colony forming fibroblast units/ml had faster and greater pain reduction.

There is one small randomized controlled clinical trial in 24 patients using the Pfirrmann grading scale for degeneration, allogeneic mesenchymal cells were transferred to the clinical cohort. Significant relief of pain was noted compared to the sham group demonstrating that allogeneic transfer may be logistically better than autogenous transfer (8).

 

Possible adverse effects
Concerns include transformation into neoplastic process. This seems to be true with embryonic stem cells which are much earlier seen in the cell lineage. Mesenchymal cells are further down the line as a committed cell type to obviate this. With in vitro culturing, there is concern for cell mutations, but this is less of a concern if it is a same day procedure, autologous and exist as when they were in the body previously. There is concern for extravasation beyond the limit of the disc and if combined with other treatments such as PRP it may promote osteogenesis. In addition, animal models may not replicate the harsh microenvironments of disc pathology where continual torsion and pressure is involved and effects and outcomes might be different (3).

In summary
There is much scientific and animal model data that stem cells remain a viable option for treatment of back pain which is one of the most common problem encountered by neurologists, neurosurgeons, orthopedic surgeons and pain management specialists. While there is much demonstrated in animal studies, clinical trials are still very sparse. This treatment, however, shows promise and despite paucity of clinical trial data, this treatment is gaining traction in practicing clinicians who treat back pain.

Given the failure with medications and even with surgery there is increased interest in alternative treatments including stem cell therapy.

Introduction/Disclaimer

Introduction/Disclaimer

References

1. Rosenberg, et al, “Bedside to bench and back to bedside: translational implications of targeted intervertebral disc therapeutics,” J. Orthop. Translat., 2017, Apr., 10:18-27.
2. Perez-Cruet, et al, “Potential of human nucleus pulposus-like cells derived from umbilical cord to treat degenerative disc disease,” Neurosurgery, 2018, Feb., doi:10.1093/neuros/nyy012
3. Zeckser, et al, “Multipotent stem cell treatment for discogenic low back pain and disc degeneration,” Stem Cell Int., 2016, doi: 10.1155/2016/3908389
4. Knezevic, et al, “Treatment of chronic low back pain – new approaches on the horizon,” J. Pain Res., 2017, May 10, 10:1111-1123
5. Orozco, et al, “Intervertebral dis repair by autologous mesenchymal bone marrow cells: a pilot study,” Transplantation, 2011, Oct., 15, 92 (7):822-8
6. Yoshikawa, et al, “Disc regeneration therapy using marrow mesenchymal cell transplantation: a report of 2 cases,” Spine, 2010, May 15, 35 (11):E475-80
7. Pettiness, et al, “Percutaneous bone cell concentrate reduces discigenic lumbar pain through 12 months,” Stem Cell, 2015, 33(1):146-156
8. Noriega, et al, “Intervertebral disc repair by allogeneic mesenchymal bone marrow cells,” Transplantation, Aug., 2017, 101(8):1945-1951.

 

 

 

 

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Peripheral neuropathy

On pluripotent stem cell research chemotherapy-induced peripheral neuropathy

Virginia Thornley, M.D., Neurologist, Epileptologist

March 1, 2018

Introduction

As more and more survivors of cancer grow in number, there is increasing interest in treatments for chemotherapy-induced toxicity. Chemotherapy-induced peripheral neuropathies are one of the most common neurotoxic side effects prevalent in cancer survivors. Attention is drawn to alternative treatments such as stem cell research as at times, this condition may be resistant to treatment with conventional agents.

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Common chemotherapeutic agents that cause neuropathy

Some of the most common chemotherapeutic agents that cause peripheral neuropathy include vincristine, oxaliplatin, cisplatin, paclitaxel. The sites most prevalent with neurotoxic effects include the dorsal root ganglion, peripheral nerves, satellite cells and Schwann cells as well as glial cells in the spinal cord.

Some mechanisms that are proposed that cause neural damage include glutamate activation, increased intracellular oxygen changes, DNA damage, altered cell repair, alteration in ion channels, change in mitochondrial metabolism and MAP kinase activation.

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Role of stem cell in chemotherapy-induced peripheral neuropathy and other novel treatment approaches

In chemotherapy for colon cancer, oxaliplatin can cause chemo-induced peripheral neuropathy in 50% of patients. In one study, pain relieving qualities of mesenchymal stem cells were studied. Rat adipose stem cells were applied to rats with chemotherapy-induced peripheral neuropathy in one animal model. An IV injection of rat adipose stem cell injected into the rate of neuropathy revealed a reduced hypersensitivity to the noxious effects. Repeated injections every 5 days produced the same results. VEGF was noted to be upregulated or vascular endothelial growth factor. When a monoclonal antibody used against this VEGF was applied there was reduced pain, suggesting a role of VEGF in pain. Adult adipose mesenchymal stem cell may represent a novel approach to alleviating pain from chemotherapy-induced peripheral neuropathy. This rat model also elucidated the role an antibody against VEGF can play in the treatment of peripheral neuropathy caused by chemotherapy.

Pain might also be influenced by increased gap junction coupling during chemotherapy. In one study, using a gap coupling blocker, the pain was alleviated in chemotherapy-induced peripheral neuropathy in mice producing an analgesic effect(3).

 

Reference:

  1. Di Cesare, et al, “Adipose-derived stem cells decrease pain in a  rat model of oxaliplatin-induced neuropathy: role of VEGF-A modulation,” Neuropharmacology, 2018, Mar., 15; 131:166-175.
  2. Carozzi, et al, “Chemotherapy-induced neuropathy: what do we know now?” Neuroscience Letter, 2015, Jun., 2(596):90-107.
  3. Warwick, et al, “The contribution of satellite glial cells to chemotherapy-induced neuropathic pain,” European Journal of Pain, 2013, Apr., 17(4):571-80.
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multiple sclerosis

Multiple sclerosis: stem cell therapy and its role in remyelination

Virginia Thornley, M.D., Neurologist

February 25, 2018

Stem cell research is a fast-growing arm of science. Multiple sclerosis is an autoimmune disease where the central nervous system is attacked as foreign. Clinical symptoms depend on the area involved, primarily in the white matter. Scientific research is being more and more directed towards agents and treatment modalities that differ from today’s immunomodulating agents given the potentially devastating side effects of the more efficacious medications. The heavy hitters tend to be more serious adverse effects.

How stem cell administration works

Umbilical cord mesenchymal stem cells may play a significant role in tissue repair and immunomodulatory processes that are important in multiple sclerosis. Stem cells divide into different types of cells which give rise to different tissues. They hold a wealth of potential in repairing damaged tissue as that found in multiple sclerosis. In one study, the mesenchymal stem cells from the umbilical cord were found with low immunogenicity. They can inhibit the multiplication of killer cells, T lymphocytes, and B lymphocytes and can inhibit the maturation of dendritic cells. Mesenchymal stem cells migrate to the site of injury and proliferate to repair damaged tissue.

Different stem cells that can be used in multiple sclerosis

Other types of stem cells are derived from hematopoeitic, embryonic, neural, spermatogonic, adipose, endometrial, Wharton jelly surrounding the umbilical cord and pluripotent-induced stem cells.

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Stem cell administration in 2 patients and reduction of abnormal MRI abnormalities

In one study, 2 patients were treated with stem cells. Clinical symptoms were reduced in the 1st patient, they were followed 8 years and found without adverse effects. The 2nd patient progressed and the timing of stem cell administration was shortened resulting in the reduction of symptoms. The number of abnormal foci seen in the MRI of the brain was less suggesting remyelination of damaged tissue within the brain. During illness, the body increases the immunogenicity with amplification of inhibitory co-stimulatory signals. With stem cell administration, this process reduces these destructive immune processes. Umbilical cord mesenchymal cells were found to inhibit IL-17c, HLA-DRB1, and IL-2 thereby protecting against an autoimmune response. The mechanism of action by which the stem cells work favors a remyelination repairing the damaged area(1).

Stem cell research in a study of 20 patients and reduction in disability

In another larger study of 20 patients, mesenchymal stem cell neural progenitor was applied. Results showed 70% had improved muscle strength and 50% improved in bladder symptoms. Improved EDSS (Expanded Disability Status Scale) was noted in 40% of patients, there were some minor adverse effects (2).

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Larger clinical randomized case control trials are needed.

References
  1. Meng, et al, “Umbilical cord mesenchymal stem cell transplantation in the treatment of multiple sclerosis,” American Journal of Translational Research, 2018, 10(1): 212-223.
  2. Harris, et al, “Phase I trial of intrathecal mesenchymal stem cell-derived neural progenitors in progressive multiple sclerosis,” EBioMedicine, 2018, Feb., pii.S2352-3964 (18)30051-3 (Epub ahead of print)
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