Wednesday, 5 June 2013

New method to improve cartilage formation from stem cells

Despite all the recent advantages in regenerative medicine, cartilage injuries still remain a challenge. Current methods to treat cartilage defects involve drilling the subchondral bone where the damage lays (microfracture) or taking a piece of cartilage from a non weight bearing area of the joint and transplanting it over the damaged area (OATS). In many cases, both approaches prove to be ineffective and the cartilage continues to deteriorate, leading to osteoarthritis. For this reason, bioengineers are constantly trying to come up with new ways to grow healthy cartilage from stem cells. Today, researchers from the University of Pennsylvania announced that they have taken an important step towards this goal.

"The broad picture, is trying to develop new therapies to replace cartilage tissue, starting with focal defects -- things like sports injuries -- and then hopefully moving toward surface replacement for cartilage degradation that comes with ageing. Here, we're trying to figure out the right environment for adult stem cells to produce the best cartilage.", said Jason Burdick, one of the two leading authors.

As we age, the health and vitality of chondrocytes - the cells that form cartilage - declines, this is why the regenerative capacity of adult chondrocytes is limited, added Robert Mauck, the second leading author.

"Stem cells, which retain this vital capacity, are therefore ideal", said Burdick.

For the past years, Burdick and his team have been studying mesenchymal stem cells (MSCs) extensively, being particularly interested in identifying specific microenvironmental signals that induce MSCs cells to differentiate.


Image of a mesenchymal stem cell
A mesenchymal stem cell

In their latest study, the research team investigated how certain conditions coax MSCs to become either adipocytes (fat-forming cells) or chondrocytes, while being encapsulated in a hydrogel, a network of polymer chains that simulates some of the conditions found in the microenviroment in which stem cells naturally grow and develop.

The first requirement to grow new cartilage is to initiate chondrogenesis, in other words to "convince" MSCs to become chondrocytes, which in turn produce the flexible connective tissue that cushions our joints. To prompt the differentiation process, the chondrocytes must be placed near together, explained Burdick.

"In typical hydrogels used in cartilage tissue engineering, we're spacing cells apart, so they're losing that initial signal and interaction. That's when we started thinking about cadherins, which are molecules that these cells use to interact with each other, particularly at the point they first become chondrocytes.", said Burdick.

To simulate this environment, the researchers used a peptide sequence that mimics these cadherin interactions, and bounded it to the hydrogels they have been using on MSCs.

"While the direct link between cadherins and chondrogenesis is not completely understood, what's known is that if you enhance these interactions early during tissue formation, you can make more cartilage, and, if you block them, you get very poor cartilage formation. What this gel does is trick the cell into thinking it's got friends nearby.", said Mauck.

To assess the efficacy of the peptide, the researchers conducted a series of experiments. First, they encapsulated MSCs into the following types of hydrogel:
  • A regular hydrogel with no peptide
  • A hydrogel with a dysfunctional, scrambled version of the peptide
  • A hydrogel with the cadherin-mimicking peptide and an antibody that blocks cadherin interactions

A week later, the researchers found that the cells within the hydrogels with the cadherin peptide had exhibited more genetic markers of chondrogenesis than the other gels did.


Picture of chondrocytes
Chondrocytes in hyaline cartilage


In another experiment, they grew hydrogels for 4 weeks, a period which was long enough for them to start developing cartilaginous tissue. This allowed them to conduct functional tests, like subjecting the gels to mechanical forces. The peptide-containing gels performed more like natural cartilage does compared to the other gels.

Finally, the researchers sectioned the gels and stained them for type-II collagen and chondroitin sulfate, molecules found in healthy cartilage. As expected, the peptide-containing gels produced more of these two markers.

"All together, these experiments provide a thorough demonstration that this cadherin signal can improve the chondrogenesis response when presented from a synthetic hydrogel." said Burdick.

"Moving forward, it will be important to see how these early cell fate decisions translate into longer term tissue function in-vivo." added Mauck.


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Reference
Bian L, Guvendiren M, Mauck RL, & Burdick JA (2013). Hydrogels that mimic developmentally relevant matrix and N-cadherin interactions enhance MSC chondrogenesis. Proceedings of the National Academy of Sciences of the United States of America PMID: 23733927 

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