Overview of the role for calreticulin in the enhancement of wound healing through multiple biological effects.
Calreticulin (CRT), an intracellular chaperone protein crucial for the proper folding and transport of proteins through the endoplasmic reticulum, has more recent acclaim as a critical regulator of extracellular functions, particularly in mediating cellular migration and as a requirement for phagocytosis of apoptotic cells. Consistent with these functions, we show that the topical application of CRT has profound effects on the process of wound healing by causing a dose-dependent increase in epithelial migration and granulation tissue formation in both murine and porcine normal and impaired animal models of skin injury. These effects of CRTare substantiated, in vitro, as we show that CRT strongly induces cell migration/wound closure of human keratinocytes and fibroblasts, using a wound/scratch plate assay, and stimulates cellular proliferation of human keratinocytes, fibroblasts, and vascular endothelial cells, providing mechanistic insight into how CRT functions in repair. Similarly, in both animal models, the histology of the wounds show marked proliferation of basal keratinocytes and dermal fibroblasts, dense cellularity of the dermis with notably increased numbers of macrophages and well-organized collagen fibril deposition. Thus, CRT profoundly affects the wound healing process by recruiting cells essential for repair into the wound, stimulating cell growth, and increasing extracellular matrix production.
Gold
Leslie I
LI
Department of Medicine, New York University School of Medicine, New York, New York 10016, USA. leslie.gold@med.nyu.edu
Rahman
Mohammad
M
Blechman
Keith M
KM
Greives
Matthew R
MR
Churgin
Samara
S
Michaels
Joseph
J
Callaghan
Matthew J
MJ
Cardwell
Nancy L
NL
Pollins
Alonda C
AC
Michalak
Marek
M
Siebert
John W
JW
Levine
Jamie P
JP
Gurtner
Geoffrey C
GC
Nanney
Lillian B
LB
Galiano
Robert D
RD
Cadacio
Caprice L
CL
D000818:Animals; D037282:Calreticulin / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006097:Granulation Tissue / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
D037282:Calreticulin; D042461:Vascular Endothelial Growth Factor A