Abstract
BackgroundFollowing tissue injury, monocytes can enter the tissue and differentiate into fibroblast-like cells called fibrocytes, but little is known about what regulates this differentiation. Extracellular matrix contains high molecular weight hyaluronic acid (HMWHA; ∼2×106 Da). During injury, HMWHA breaks down to low molecular weight hyaluronic acid (LMWHA; ∼0.8–8×105 Da).Methods and FindingsIn this report, we show that HMWHA potentiates the differentiation of human monocytes into fibrocytes, while LMWHA inhibits fibrocyte differentiation. Digestion of HMWHA with hyaluronidase produces small hyaluronic acid fragments, and these fragments inhibit fibrocyte differentiation. Monocytes internalize HMWHA and LMWHA equally well, suggesting that the opposing effects on fibrocyte differentiation are not due to differential internalization of HMWHA or LMWHA. Adding HMWHA to PBMC does not appear to affect the levels of the hyaluronic acid receptor CD44, whereas adding LMWHA decreases CD44 levels. The addition of anti-CD44 antibodies potentiates fibrocyte differentiation, suggesting that CD44 mediates at least some of the effect of hyaluronic acid on fibrocyte differentiation. The fibrocyte differentiation-inhibiting factor serum amyloid P (SAP) inhibits HMWHA-induced fibrocyte differentiation and potentiates LMWHA-induced inhibition. Conversely, LMWHA inhibits the ability of HMWHA, interleukin-4 (IL-4), or interleukin-13 (IL-13) to promote fibrocyte differentiation.ConclusionsWe hypothesize that hyaluronic acid signals at least in part through CD44 to regulate fibrocyte differentiation, with a dominance hierarchy of SAP>LMWHA≥HMWHA>IL-4 or IL-13.
Highlights
After tissue injury, local fibroblasts proliferate to repair the wound [1,2]
Since low molecular weight hyaluronic acid (LMWHA) increases during tissue injury [24], in this report we examined the effect of hyaluronic acid on fibrocyte differentiation
high molecular weight hyaluronic acid (HMWHA) has a range of molecular masses with a peak at 26106 Da and LMWHA has a range of molecular masses with a peak at 7.56105 Da; as described below, these sizes were verified by gel electrophoresis
Summary
Bone-marrow-derived progenitor cells infiltrate the injured site and differentiate into fibroblast-like cells called fibrocytes [3]. Fibrocytes can differentiate from purified CD14+ peripheral blood monocytes, but fibrocytes lose expression of CD14 [4,5,6,7,8]. Other studies suggest that fibrocytes differentiate from a population of bonemarrow derived CD45+ CXCR4+ cells found in peripheral blood [9,10,11]. Monocytes can enter the tissue and differentiate into fibroblast-like cells called fibrocytes, but little is known about what regulates this differentiation. Extracellular matrix contains high molecular weight hyaluronic acid (HMWHA; ,26106 Da). HMWHA breaks down to low molecular weight hyaluronic acid (LMWHA; ,0.8–86105 Da)
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