Topical GDF11 accelerates skin wound healing in both type 1 and 2 diabetic mouse models
Introduction
Patients with diabetes mellitus (DM) are highly fragile to various environmental insults and skin damage is one of the most frequently occurred problems in DM subjects because of the non-healing property of skin wounds. Diabetic wound (DW) developing into diabetic foot ulcers (DFU) is the leading cause of hospital admission in diabetic patients, significantly adding to global economic, social, and clinical burdens worldwide [1]. Compared to euglycemic subjects, diabetic patients have more than a 100 times greater risk of suffering a lower extremity amputation due to non-healing DFU. However, effective treatment of diabetic wounds has been lacking [2].
As one of the relatively effective methods, growth factor substances have been shown to be effective in promoting wound healing. They can play a role in promoting angiogenesis and promoting fibroblast proliferation, thereby achieving wound healing. Including platelet-derived growth factor (PDGF), which is the only drug approved by the US Food and Drug Administration, basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). Growth differentiation factor 11 (GDF11), a member of the transforming growth factor β (TGF-β) superfamily, is a regulator of cell growth and differentiation in both embryonic and adult tissues [3]. It has emerged as a youth factor that produces anti-aging effects in both animals and humans although contradictory or contrary observations [4]. Our recent study demonstrates that topical application of GDF11 accelerates the healing process of diabetic skin wounds via accelerating vasculogenesis suggesting GDF11as a potential therapeutic drug for would healing in patients (unpublished observations). Nonetheless, the presence of a recognition site of Furin, a paired basic amino acid cleaving enzyme or a protease, at Arg312 of wild-type GDF11 could make this protein susceptible to enzyme digestion at the disulfide bond at between positions 313 and 372 thereby impairing its cellular stability and activity. Such an issue could hinder the translational potential of GDF11 for clinical applications. To tackle this problem, we carried out deletion mutation of GDF11 by removing N-terminal 14 amino acids (AA) from natural GDF11 to become a 95-AA peptide (Supplementary Fig. S1). Such a truncation aims to delete the Furin recognition site at Arg312 while retaining the intact disulfide bond, thereby enhancing the cellular stability of this protein [5]. Our previous experimental study has confirmed the greater efficacy of the truncated version of GDF11 (tGDF11) than natural GDF11 in activating Smad2/3, the typical downstream signalling mediator of GDF11 [5].
The present study was set out to investigate the effects of tGDF11 on diabetic skin would healing and compare the relative efficacies of tGDF11 with those of wild-type or natural GDF11, PDGF, bFGF and EGF in full-thickness skin wound healing. In addition, we also investigated fibrosis-promoting effect of GDF11 as an alternative mechanism for its wound healing-accelerating property. Our experiments were carried out on a mouse model of pharmacologically induced type 1 DM (T1DM) and genetically engineered type 2 diabetic db/db mice (T2DM).
Section snippets
Ethics statement
The experimental procedures involving the use of animals in this study were approved by the Animal Care and Use Committee of Harbin Medical University (HMUIRB-2008-06), and conformed to the Guidelines for the Care and Use of Laboratory Animals set forth by the US National Institutes of Health (NIH Publication No. 85–23, revised 1996).
Type 1 DM mice model
Kunming male mice (29–31 g) were injected 1.8 mg/g streptozocin (STZ; Sigma, USA) after fasted and DM model was considered successfully established with blood
GDF11 accelerates diabetic wound healing in T1DM mice
To explore the role of GDF11 in skin would healing, we began with a mouse model of T1DM or pharmacological T1DM induced by injection of streptozocin (STZ). We then verified the successful establishment of T1DM by monitoring the changes of fasting blood glucose (FBG) levels (Supplementary Fig. S2). We subsequently confirmed the bioactivities of natural and truncated GDF11s used in our experiments in human skin fibroblasts (HSFs) by demonstrating the remarkable activation of Smad2/3 (
Discussion
The non-healing nature of diabetic wounds affects millions of people worldwide, and offers a substantial unmet clinical need. The aims of the present study was to examine the efficacy of GDF11 in controlling diabetic skin wound healing by comparing with the effects of three well-recognized wound healing-promoting growth factors (including PDGF, bFGF and EGF) and of another myokine growth factor myostatin (GDF8) and to shed light on the cellular and molecular mechanisms for its beneficial
Declaration of competing interest
All the authors declare no conflict of interest.
Acknowledgements
This work was supported in part by the National Key R&D Program of China (2017YFC1702003), the National Natural Science Foundation of China (81970320, 81570399, 81670238, and 81773735).
References (21)
- et al.
Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy
Cell
(2013) - et al.
Recent developments in myofibroblast biology: paradigms for connective tissue remodeling
Am. J. Pathol.
(2012) - et al.
Connective tissue growth factor (CTGF) from basics to clinics
Matrix Biol., null
(2018) - et al.
Activin a promotes myofibroblast differentiation of endometrial mesenchymal stem cells via STAT3-dependent Smad/CTGF pathway
Cell Commun. Signal.
(2019) - et al.
Effects of structurally stabilized EGF and bFGF on wound healing in type I and type II diabetic mice
Acta Biomater.
(2018) Formation and function of the myofibroblast during tissue repair
J. Invest. Dermatol.
(2007)- et al.
Keratinocyte-fibroblast interactions in wound healing
J. Invest. Dermatol.
(2007) - et al.
TGF-β targets the Hippo pathway scaffold RASSF1A to facilitate YAP/SMAD2 nuclear translocation
Mol. Cell
(2016) - et al.
Topical antimicrobial agents for treating foot ulcers in people with diabetes
Cochrane Database Syst. Rev.
(2017) - et al.
Pharmacologic treatment options for type 1 diabetes: what’s new?
Expet Rev. Clin. Pharmacol.
(2019)
Cited by (9)
GDF11 mitigates high glucose-induced cardiomyocytes apoptosis by inhibiting the ALKBH5-FOXO3-CDR1as/Hippo signaling pathway
2024, Biochimica et Biophysica Acta - Molecular Cell ResearchGrowth differentiation factor 11: A new hope for the treatment of cardiovascular diseases
2023, Cytokine and Growth Factor ReviewsRecent advances in the role of Yes-associated protein in dermatosis
2023, Skin Research and TechnologyThe regulatory effect of growth differentiation factor 11 on different cells
2023, Frontiers in Immunology