Stem Cell Study Suggests Novel Mechanism of Action in Knee Osteoarthritis

By Thomas Crocker
Sunday, September 1, 2019

Autologous bone marrow mesenchymal stromal cells (MSCs) are safe and efficacious in treating knee osteoarthritis (OA), and — in an apparently novel finding — they may reduce inflammation and modulate immune cells that contribute to the condition, Canadian researchers report.

In recent years, scientists have studied MSCs as a potential treatment for OA of the knee out of a desire to fill a therapeutic gap in the disease process, according to Sowmya Viswanathan, PhD, Assistant Professor at the Institute of Biomaterials and Biomedical Engineering and the Division of Hematology, Department of Medicine, at the University of Toronto, and Affiliate Scientist with the Arthritis Program, Krembil Research Institute, University Health Network.

“There was a lot of interest in using [MSCs] for OA patients, who really don’t have any disease-modifying treatments available to them for a number of years,” Viswanathan says. “They have to have symptom-modification injections, they take analgesics, and then, eventually, when [cartilage] deteriorates, they become candidates for joint replacement surgery. But there’s this really big gap in between where there is not much available. They … have to trudge through this trough of managing and living with pain and disability.”

Several small-scale clinical studies deemed MSCs safe and effective at relieving pain associated with knee OA. In a 2016 study, researchers in India found that individuals who received a 25-million-cell dose of allogeneic MSCs displayed a trend toward improvement in knee pain. A 2015 Spanish study demonstrated that allogeneic MSCs improved pain and cartilage quality. Those findings corroborated an earlier study from Spain involving autologous MSCs.

Hints of a Dose-Response Effect

To assess the safety of MSCs, as well as learn more about dosing, mechanisms of action and donor selection, Viswanathan and collaborators conducted the first Canadian clinical trial using patient-derived MSCs to treat knee OA.

Twelve individuals with end-stage OA in four, three-person cohorts received a single injection of their own bone marrow MSCs in a 1-million-cell, 10-million-cell or 50-million-cell dose. The participants followed up with the researchers in clinic eight times over a 24-month period. The team used a variety of methods to assess the cells’ effects, including patient-reported outcome measures, inflammation biomarkers and MRI to look for changes to cartilage. The findings appear in STEM CELLS Translational Medicine.

One year after treatment, participants reported significant improvement in pain, symptoms, quality of life and knee stiffness. Those who received the highest dose of MSCs — 50 million cells — experienced the most improvement, suggesting a dose-response effect.

“What was not surprising — and something we hypothesized — was the cells would be safe,” says Jaskarndip Chahal, MD, MSc, MBA, Assistant Professor in the Department of Surgery at University of Toronto Orthopaedic Sports Medicine and University Health Network Arthritis Program, who was part of the research team. “We had no [serious] adverse events.”

MRI did not reveal cartilage regeneration, as had been observed in other studies, possibly due to dosing and donor variations or the inclusion of patients with end-stage arthritis. To Viswanathan, a striking finding was the heterogeneity of gene expression in different participants’ MSCs and its effect on outcomes.

“We were able to look at some genes that were expressed in these cells, and we found that when some of these genes were expressed at high levels, then the patient went on to do really well,” Viswanathan says. “When the starting gene level was not very high in these patients, they didn’t do as well, so it seemed like one of the factors that determined how well patients did was … the quality of their cells and how they varied.”

That, Viswanathan says, points to the importance of careful patient and donor selection.

Evidence of Anti-Inflammatory Effects

MSCs appeared to improve synovial inflammation, with the most significant effect in patients who received the highest dose of cells. Levels of pro-inflammatory cells in the synovial fluid decreased three months after treatment. The anti-inflammatory and immunomodulatory mechanism of action of MSCs in OA may be a first-of-its-kind clinical finding, according to the team.

The interaction between MSCs and immune cells was not unexpected — the researchers had observed the two interacting in the laboratory — but Viswanathan says it was gratifying to see the team’s hypothesis that MSCs reduced the number of immune cells and the factors they secreted, confirmed in a clinical setting. Reducing immune cells, she says, is important not just because it can improve symptoms, but also because it may slow disease progression.

Anthony Atala, MD, Director of the Wake Forest Institute for Regenerative Medicine, says it is too soon to draw any clinical implications from the study, given its small size, but it provides a basis for future inquiry.

“[T]his study shows [MSCs] are safe,” says Dr. Atala, who was not involved in the research. “[A]lthough they do not lead to actual cartilage regeneration, they do have the potential to decrease inflammation.”