High and low molecular weight hyaluronic acid differentially regulate human fibrocyte differentiation.
BACKGROUND
Following 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; ∼2×10(6) Da). During injury, HMWHA breaks down to low molecular weight hyaluronic acid (LMWHA; ∼0.8-8×10(5) Da).


RESULTS
In 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.


CONCLUSIONS
We 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.
Department of Biochemistry and Cell Biology, MS-140, Rice University, Houston, Texas, United States of America.
Anu S
AS
Maharjan
Darrell
D
Pilling
Richard H
RH
Gomer
D000328:Adult; D000906:Antibodies / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry* / Q000494:pharmacology*; D006821:Hyaluronoglucosaminidase / Q000494:pharmacology; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D008970:Molecular Weight; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D000683:Serum Amyloid P-Component / Q000494:pharmacology
D000906:Antibodies; D018960:Hyaluronan Receptors; D018793:Interleukin-13; D000683:Serum Amyloid P-Component; D015847:Interleukin-4; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase