The discovery of some unusual behavior in adult heart cells after injury may point to treatment for fibrosis, the slow organ scarring that eventually causes heart failure.
The cells are endothelial cells, which normally provide an inner lining for blood vessels. According to new work from the lab of Raghu Kalluri, HMS associate professor of medicine at Beth Israel Deaconess Medical Center, a heart attack or other insult can turn the cells into fibroblasts, the creators of scar tissue.
Scarring fibroblasts are not found in the normal heart in large numbers, and where they come from during fibrosis has been a mystery.
“Our results indicate that injury sets up an environment of cytokines and other factors that promote the change of endothelial cells into fibroblasts,” said Kalluri. The transition is one that occurs during embryonic heart development, but it has not been seen before in adult tissues.
The investigators go on to show that the same cytokine that induces the embryonic switch, TGF-beta1, contributes to heart fibrosis in adult mice. Likewise, a known inhibitor of embryonic heart development, bone morphogenic protein-7, inhibited the switch, reduced fibrosis, and improved heart function in the animals modeling a heart attack or rejection of a transplanted heart.
The same researchers have documented a similar transition in other organs prone to fibrosis, including the lung, liver, and kidney. This raises the possibility that targeting the TGF/BMP pathway could lead to a broad-based treatment for fibrosis that occurs in many organs and diseases, Kalluri said.
According to Kalluri, much of the mechanistic credit for this new understanding of fibrosis belongs to the late Elizabeth Hay, the Louise Foote Pfeiffer professor emerita of embryology in the Department of Cell Biology, who passed away in August (see obituary). Hay discovered what is called the epithelial-to-mesenchymal transformation (EMT) in embryonic development. (The mesenchyme gives rise to fibroblasts.) Her work started an entire field in cell biology devoted to studying the EMT.
Kalluri remembers Hay as a pioneer in studies of the extracellular matrix and EMT, an ardent supporter of his work, and a dear colleague. “We were friends and neighbors. It was very endearing how she constantly would call and encourage us to pursue this area of research. I will miss her collegiality,” he said. “She pushed the idea that the EMT was involved not only in development but also in disease, and I want to acknowledge her role in this work.”
The study appeared in the August Nature Medicine.
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