Discoidin domain receptors and their ligand, collagen, are temporally regulated in fetal rat fibroblasts in vitro.
The biochemical regulation of collagen deposition during adult cutaneous wound repair is poorly understood. Likewise, how collagen is perceived and modulated in fetal scarless healing remains unknown. Recently, discoidin domain receptors-1 and 2 (DDR1 and DDR2) with tyrosine kinase activity have been identified as novel receptors for collagen. In light of these findings, it was speculated that the production of collagen receptors DDR1 and DDR2 by fetal fibroblasts may be temporally regulated to correlate with the ontogeny of embryonic scar formation. More specifically, because DDRs directly bind collagen and transmit the signals intracellularly, it was hypothesized that they may play an important role in fetal scarless healing by ultimately regulating and modulating collagen production and organization. As part of a fundamental assessment to elucidate the role of DDRs in scarless fetal wound repair, the endogenous expression of DDR1, DDR2, collagen I, and total collagen, as a function of fetal Sprague-Dawley rat skin fibroblasts of different gestational ages, representing scar-free (<E16.5 days) and scar-forming (>E16.5) periods was determined. Using explanted dermal fibroblasts of gestational days E13.5, E16.5, E18.5, and E21.5 (term gestation = 21.5 days) fetuses (n = 92), [3H]proline incorporation assay and Northern and Western blotting analysis were performed to compare the expressions of these molecules with scar-free and scar-forming stages of embryonic development. These results revealed a pattern of increasing collagen production with increasing gestational ages, whereas DDR1 expression decreased with increasing gestational age. This observation suggests that elevated levels of DDR1 may play an important role in scarless tissue regeneration by early gestation fetal fibroblasts. In contrast, DDR2 was expressed by fetal rat fibroblasts at a similar level throughout gestation. These data demonstrate for the first time the temporal expression of collagen and DDR tyrosine kinases in fetal rat fibroblasts as a function of gestational ages. Overall, these data suggest that differential temporal expression of the above-mentioned molecules during fetal skin development may play an important role in the ontogeny of scar formation. Future studies will involve the characterization of the biomolecular functions of these receptor kinases during fetal wound repair.
Chin
G S
GS
Department of Surgery, Stanford University School of Medicine, Stanford, California, USA.
Lee
S
S
Hsu
M
M
Liu
W
W
Kim
W J
WJ
Levinson
H
H
Longaker
M T
MT
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D002921:Cicatrix / Q000378:metabolism / Q000503:physiopathology; D003094:Collagen / Q000096:biosynthesis* / Q000502:physiology; D000070818:Discoidin Domain Receptors; D005333:Fetus / Q000378:metabolism / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism*; D005865:Gestational Age; D016023:Integrins / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D038981:Receptors, Collagen; D011975:Receptors, Mitogen / Q000378:metabolism* / Q000502:physiology; D012867:Skin / Q000166:cytology; D014945:Wound Healing / Q000502:physiology*
D016023:Integrins; D012333:RNA, Messenger; D038981:Receptors, Collagen; D011975:Receptors, Mitogen; D003094:Collagen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases