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In this study, Dr. Koga and his team focused on identifying the most effective cell therapy for cartilage injuries. To do this, they conducted in vitro and in vivo comparisons of four different types of rabbit MSCs—bone marrow, synovium, adipose, and muscle—under various conditions and with different parameters.

AAOS Now

Published 7/1/2008
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Annie Hayashi

Putting MSCs to the test

Which stem cell has most chondrogenic potential?

“Mesenchymal stem cell (MSC) therapy is very attractive for cartilage repair because so many stem cells can be obtained without damaging the normal cartilage,” said Hideyuki Koga, MD, PhD, during his presentation at the 2008 annual meeting of the Orthopaedic Research Society (ORS). “We found that synovial stem cells, when compared with the others we tested, had the highest chondrogenic potential in vitro and in vivo.”

Hideyuki Koga,
MD, PhD

“The data we gathered,” Dr. Koga explained, “enabled us to determine the suitable conditions for MSC therapy for cartilage defects and will advance clinical application of MSC-based cell therapy for cartilage regeneration.”

Comparing chondrogenic potential
In vitro chondrogenic potential was evaluated through the use of pellet cultures. Synovium-derived MSCs formed pellets that were larger and heavier than those formed by bone marrow-, adipose-, and muscle-derived MSCs.

MSCs from synovium and bone marrow cells had adequate levels of metachromasia, while the adipose and muscle cells did not.

“Our results suggested that MSCs with poor chondrogenic potential in vitro,” said Dr. Koga, “would not be able to differentiate into chondrocytes when the cells are transplanted into the cartilage defect.”

To test that theory, each type of MSC was suspended in a collagen gel and transplanted into cartilage defects with a periosteal patch. After 4 weeks, the cartilage defects transplanted with synovium and bone marrow MSCs had significantly more cartilage matrix and higher histologic scores than those transplanted with adipose and muscle MSCs, as well as higher histologic scores.

“When we transplanted the synovium-derived cells,” explained Dr. Koga, “the border between the regenerated cartilage-like tissue and the subchondral bone moved up and closed to the native height at 12 weeks.”

He also reported that the regenerated cartilage matrix seemed stable and held its metachromasia. The histologic score also improved at 12 weeks when compared with 4 weeks.

Of the four MSC cell types tested, synovium-derived cells had the highest chondrogenic potential.

Impact of cell density
Since the synovium-derived cells had consistently demonstrated the most chondrogenic potential, Dr. Koga and his investigators transplanted the synovium-derived cells at different densities to assess their effect on in vivo chondrogenic potential. After 4 weeks, the defects treated with a higher density of cells had more cartilage matrix and higher histologic scores than those treated with a lower density of cells.

“Higher cell density will promote healing of cartilage defects more effectively;” Dr. Koga explained. “It is not always possible, however, to prepare a sufficient number of cells. The advantage of synovium-derived MSCs is their predominant proliferation potential.”

Effect without the periosteal patch
Although periosteal coverage is commonly used to “fix” cells or cell/scaffold composite in cartilage, Dr. Koga conceded that transplanting MSCs without the periosteal patch would be preferable. The invasive procedure required to harvest the periosteum may result in complications such as hypertrophy or ossification.

When he tested the effectiveness of synovium-derived cells/gel composites with and without a periosteal patch, however, he found that the cartilage that developed without the patch was “lower in height” than that transplanted with the patch. In addition, the surface regularity score in the nonperiosteal patch group was significantly “worse” than the group with the patch.

Despite these limitations, Dr. Koga and his team found that transplanted MSCs in collagen gel differentiated into chondrocytes and produced cartilage matrix whether a periosteal patch was used or not.

The transplanted composites, however, were not able to sufficiently expand to fill the entire defect. Dr. Koga attributed this result to “the influence of the collagen gel, which may prevent production or extension of cartilage matrix.”

He suggested that the periosteal patch would be needed to fill the defects to the original height of the joint surface. “Development of novel transplantation procedures without periosteum and scaffold would be further expected,” he said.

Dr. Koga’s coauthors for “Comparison of mesenchymal tissues-derived stem cells for in vivo chondrogenesis: Suitable conditions of cell therapy for rabbit cartilage defects” are Takeshi Muneta, MD, PhD; Tsuyoshi Nagase, MD, PhD; Akimoto Nimura, MD, PhD; Young-Jin Ju, MD, PhD; Tomoyuki Mochizuki, MD, PhD; and Ichiro Sekiya, MD, PhD.

Annie Hayashi is the senior science writer for AAOS Now. She can be reached at hayashi@aaos.org