Endotrophin, a fibroblast matrikine, may be a driver of fibroblast activation in fibro-inflammatory diseases
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Alexander Lynge Reese‐Petersen, Federica Genovese, Lei Zhao, G. Banks, David A. Gordon, M.A. Karsdal
A small fragment released from the heart’s supporting tissue may do more than mark trouble. It may help push heart cells to build the very scar-like material that makes the heart work poorly.
Extracellular matrix proteins harbor signaling domains that once released from the parent molecule can trigger cellular responses. One of these molecules is endotrophin, a type VI collagen derived fragment, whose circulatory levels have been associated to an increased risk of adverse outcome in heart failure with preserved ejection fraction (HFpEF). Here we show that the stimulation of human cardiac fibroblasts by endotrophin upregulates the synthesis of type I collagen, the main interstitial collagen that accumulates in the myocardium during fibrogenesis. These data provide a possible mechanistic explanation for the relation between circulating endotrophin levels and risk of outcome in HFpEF.
Transcript
A small fragment released from the heart’s supporting tissue may do more than mark trouble. It may help push heart cells to build the very scar-like material that makes the heart work poorly. Heart failure with preserved ejection fraction is a varied condition affected by tissue scarring and disturbed metabolism, both of which increase the risk of a bad outcome.
There is a strong medical need for blood markers that reflect tissue scarring and add to current ways of judging risk and biological problems. Understanding disease-activated fibroblasts and how they contribute to illness is becoming increasingly important.
Over the past decade, growing attention has focused on endotrophin, a molecule derived from type six collagen. The supporting material around cells can contain signaling parts that, once released from a larger molecule, trigger responses in cells. Endotrophin is one of these molecules.
Its levels in the blood have been linked with a higher risk of a bad outcome in heart failure with preserved ejection fraction. To investigate this possible relationship, human heart fibroblasts were grown in a simplified laboratory system. After exposure to endotrophin, the cells showed a five-fold increase in the production of type one collagen.
This matters because a signal linked to heart scarring directly prompted heart-supporting cells to produce more type one collagen, the main structural protein that can stiffen heart tissue. At the strongest level tested, production was five times that seen without the signal.
Type one collagen is the most abundant kind of collagen in the heart muscle, and its increase could explain how endotrophin might drive scarring by directly activating fibroblasts. Higher fibroblast activity and more endotrophin in the heart muscle could impair heart function and contribute to heart failure with preserved ejection fraction and other scarring diseases.
The experiment is limited because the cell system was simple. Further studies need to test endotrophin in more complex systems and connect blood levels with increases in affected tissues, while clarifying whether it truly drives scarring. In summary, endotrophin could increase the amount of scar-like material in the heart by activating fibroblasts and increasing their production of type one collagen.
That possible chain offers a biological explanation for why higher endotrophin levels may be linked with worse outcomes in heart failure with preserved ejection fraction and other diseases involving inflammation and scarring. The study suggests that endotrophin can activate heart-supporting cells and increase collagen production, offering a possible link between a blood signal and worsening heart stiffness.
But this still needs testing in more realistic tissues and patients.
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