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Better Fibroblast Differentiation

October 26, 2010

Differentiation of mesenchymal stem cellsThere is an old saying, “Freedom is just another word for . . . fill in the blank.” The First Amendment, a two-lane open highway, no credit card debt, you name it. The idea being, the concept of freedom is so broad and subjective that today it typically means different things to different people. In biology, the same fill-in-the-blank phenomenon is true for the fibroblast, the most common cell type of the body’s connective tissues and a key player in their repair. These cells are so ubiquitous, so biologically diverse, and yet lacking in unique surface markers to easily confirm their identity that scientists sometimes assume that any uncharacterized cell that looks and acts like a fibroblast must be a fibroblast. The decades-long lumping of all things fibroblast-like into one general category raises an obvious question. What is a fibroblast . . . really? Finding the answer, like the true meaning of the word freedom, means going back to discover its origins.

In the September 1 issue of The Journal of Clinical Investigation, NIDCR grantees and colleagues go back and make some key discoveries. They show in laboratory studies that mesenchymal stem/stromal cells (MSCs) isolated from adult bone marrow do indeed yield a subset of fibroblastic lineages among the other heterogeneous bone and cartilage-producing colonies. This finding indicates that fibroblasts originate from mesenchyme, the source of the body’s connective tissue. Some previously had wondered whether fibroblasts already present in the typically heterogeneous MSC cell culture might be the mistaken source.

Importantly, the researchers showed that when MSCs are stimulated in culture with a protein called connective tissue growth factor, or CTGF, they tend to favor the production of stable fibroblastic lineages. In fact, two out of every three cell lineages was fibroblastic. The scientists found that the fibroblast cell lines were stable for further replication and study; moreover, within four weeks of treatment with CTGF, the MSCs largely lost their ability to reprogram themselves to form bone and cartilage-producing cells.

The researchers then determined that fibroblasts don’t differentiate with a bang. They do so in a gradual, step-wise fashion that is observable in the patterns of protein markers displayed on their cell surface. That is, their initial cell lines arose lacking the a-SMA protein marker, the hallmark of a myofibroblast. (While fibroblasts play an important role in normal wound healing, myofibroblasts are associated with excessive scarring.) When the scientists stimulated the fibroblasts with TGF-b, a growth factor that affects cellular proliferation, differentiation, and other basic functions, the cells then transitioned into myofibroblasts that displayed the hallmark a-SMA protein. Collectively, their data suggested that fibroblastic differentiation, connective tissue repair, and fibrosis (the formation of excessive tissue) must be three distinct processes. Their data also suggested the new possibility of targeting fibroblasts with CTGF during the repair process to push them toward a desired outcome that could make wound healing more predictable.

To put this idea to a first test, the researchers turned to an established rodent model for craniosynostosis. This common human cranial condition is characterized by the premature fusion, or mineralization, of the fibrous sutures that naturally stitch the large, plate-like calvarial bones into place like squares in a quilt to form a normally shaped skull. Children born with this condition may develop a malformed face, and the premature fusion produces an irregularly shaped skull that typically requires surgery to remove the sutures and reshape the calvarial bones. In their first test, the scientists used a tissue engineering approach to microencapsulate stores of CTGF for time-release in the skulls of the rodents during development. The results were striking. The scientists found that the slow release of CTFG alone induced connective tissue repair, or fibrogenesis, and restored the normal shape and anatomic structure of the calvarial sutures. Later, under the microscope, the sutures appeared to consist of fibroblast-like cells where sutures interact with bone. In the rodents that were not treated with CTGF, the sutures prematurely mineralized as expected. The findings suggest the possibility of a minimally invasive, localized surgery to correct craniosynostosis that perhaps one day could provide an alternative to highly invasive surgeries to reshape multiple skull bones.

The authors concluded, “These findings suggest that calvarial suture is composed of mesenchymal cells that readily differentiate into fibroblastic cells and undergo fibrogenesis upon CTGF stimulation, in addition to differentiation into other mesenchymal lineages. Fibroblastic differentiation of calvarial mesenchymal cells provides the motivation for our in vivo approach for microencapsulated delivery of CTGF to promote fibrogenesis in connective tissue healing.”

  • CTGF directs fibroblast differentiation from human mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury model, Lee CH, Shah S, Moioli EK, Mao JJ. J Clin Invest, Sept 1, 2010;120(9):3340-3349.

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This page last updated: February 26, 2014