Inhibiting the differentiation of myocardiocytes by hyaluronic acid.
BACKGROUND
In vitro experimentation found that wounded midgestation fetal mouse hearts heal scarlessly. Scarless repair occurs in an environment enriched in hyaluronic acid (HA), while in the absence of HA and the inclusion of hyaluronidase (HAdase), repair by scarring occurs. Excess HA downregulates the expression of the specific HA receptor, RHAMM (receptor for HA-mediated motility). The expression of RHAMM and the migration of cardiac cells from fetal heart explants were investigated in the presence of excess HA and added HAdase.


METHODS
Hearts from Gestational Day 15 fetal mice (term = 20) were cut into four fragments, established as explant cultures, and assigned to one of three treatment groups: 400 micrograms/ml HA, 50 U/ml HAdase, or saline. Cellular outgrow was recorded at Day 7. The character of the migrating cells (fibroblast-like or myocardiocyte) was determined by immunostaining for filamentous actin (f-actin, microfilaments) or desmin (intermediate filaments). The expression of RHAMM was documented also.


RESULTS
The inclusions of HA stimulated cell migration and proliferation, perpetuated cells as immature myocardiocytes, and blocked the expression of RHAMM. The inclusion of HAdase limited cell migration and proliferation, promoted the differentiation of cells into myocardiocytes, and increased the number of cells expressing RHAMM.


CONCLUSIONS
Increased concentrations of HA promoted the proliferation and migration of an immature population of myocardiocytes. On the other hand the inclusion of HAdase inhibits the migration and proliferation of cells and promotes the appearance of myocardiocytes with a fibroblast-like morphology. The speculation is that excess HA may promote proliferation and migration of immature myocardiocytes into a heart defect, leading to replacement of lost myocardium with contractile tissue rather than dysfunctional scar.
Iocono
J A
JA
Department of Surgery, Milton S. Hershey Medical Center, College of Medicine, Hershey, Pennsylvania 17033, USA.
Bisignani
G J
GJ
Krummel
T M
TM
Ehrlich
H P
HP
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005455:Fluorescent Antibody Technique; D005456:Fluorescent Dyes; D005865:Gestational Age; D006321:Heart / Q000196:embryology*; D006820:Hyaluronic Acid / Q000494:pharmacology*; D006821:Hyaluronoglucosaminidase / Q000494:pharmacology; D051379:Mice; D009206:Myocardium / Q000166:cytology*; D009924:Organ Culture Techniques; D010590:Phalloidine; D011247:Pregnancy; D012235:Rhodamines
D005456:Fluorescent Dyes; D012235:Rhodamines; D010590:Phalloidine; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase