Calreticulin exploits TGF-β for extracellular matrix induction engineering a tissue regenerative process

Area of Science:

• Biochemistry
• Regenerative Medicine
• Dermatology

Background:

• Extracellular calreticulin (eCRT) is an ER chaperone protein.
• Topical eCRT enhances wound healing and tissue regeneration in animal models.
• eCRT promotes epidermal appendage neogenesis and reduces scarring.

Purpose of the Study:

• To elucidate the mechanisms by which eCRT induces extracellular matrix (ECM) formation.
• To investigate the signaling pathways involved in eCRT-mediated ECM synthesis.

Main Methods:

• In vitro studies using human dermal fibroblasts (HDFs) and neonatal fibroblasts (HFFs).
• Utilized TGF-β canonical signaling, Smad2/3 activation, and LRP1 inhibition (RAP).
• Compared responses in wild-type and calreticulin (CRT) null mouse embryo fibroblasts (MEFs).

Main Results:

• eCRT strongly induces collagen I, fibronectin, elastin, and α-smooth muscle actin via TGF-β/Smad2/3 signaling.
• LRP1 inhibition blocks eCRT-induced ECM production.
• eCRT induces TGF-β3 via LRP1, followed by intracellular CRT (iCRT)-dependent TGF-β1 and ECM induction.
• CRT null MEFs do not respond to eCRT, confirming CRT's role.

Conclusions:

• eCRT induces ECM synthesis through LRP1 and TGF-β signaling pathways.
• eCRT initiates a cascade involving TGF-β3 and subsequently TGF-β1 for ECM production.
• eCRT and iCRT converge on ECM induction, with eCRT potentially attenuating fibrosis for regeneration.