What is GDF-11? It’s the “rejuvenating” factor of mice fame.

Rejuvenating growth factor

a.k.a. TGF-β1 (Transforming Growth Factor beta 1), GDF-11

INCI Name  sh-Polypeptide-22, skin protectant

Growth differentiation factor 11 (GDF-11) is a protein that regulates stem cell function, promoting cellular repair in the epidermis and dermis, as well as in other organs.  GDF-11 induces collagen I, collagen III, and elastin production in skin fibroblasts and appears to reduce skin inflammation. It’s a very promising growth factor, and one that we, at Skin Active Proteins, will soon be able to offer to the skin care industry.

GDF-11 was identified during the investigation of how blood donated by a young mouse could help rejuvenate the function of the older mouse. In heterochronic parabiosis, the circulatory systems of an old and a young mouse are merged. A blood “factor” from the young mouse increased blood flow, neural stem cell proliferation, and skeletal muscle rejuvenation in the old mouse.

Skin aging and GDF-11

Skin aging is a multi-factorial process that affects every phase of its biology and function. The expression profiles of inflammation-related genes in resident immune cells show that these cells have a strong capacity to regenerate adult skin stem cells and produce endogenous factors such as GDF11. GDF11 appears to be the key to progenitor cell proliferation and differentiation. The preservation of youthful phenotypes has been linked to the presence of GDF11 in various human tissues, and in the skin, this factor inhibits inflammatory responses. The protective role of GDF11 depends on a multi-factorial process implicating various types of skin cells, such as keratinocytes, fibroblasts, and inflammatory cells.

Mechanism of action of GDF-11

Like other members of the TGF-β superfamily, GDF11 regulates cell signaling by binding to activin receptor types I and II (Figure).

Figure. Schematic overview of the skin-protecting properties of GDF11. Mature GDF11 binds to activin receptor II (ActRII), including ActRIIA and ActRIIB, and then recruits activin receptor I (ActRI), including ALK4, and ALK5. Members of the Smad family of transcription factors are important intracellular messengers. The type I receptor subsequently phosphorylates Smad 2 or 3, allowing this complex to associate with Smad 4. This Smad complex, Smad2/3/4, is then localized to the nucleus. The Smad complex acts in the nucleus on target genes, regulating transcription. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway (PI3K/AKT), p27kip1, and IL-23 are implicated. Heat shock proteins (HSPs) and antioxidant enzymes are produced. Foxos translocate to the nucleus, where they activate gene expression programs. Foxo3 is involved in counteracting oxidative stress. Gene expression is modified after stimulation of the transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) channels.From  Rochette et.al. (2020).

Fibroblast implantation plays a crucial role in skin regeneration and wound healing; human dermal fibroblasts are important in this process because they secrete type I collagen and cytokines. When comparing fibroblasts originating from adult donors as compared to neonatal fibroblasts, it was found that GDF11 expression and activity were decreased. The induction of collagen I and III was the primary effect of GDF11 in both adult and neonatal fibroblasts, mediated by Smad signaling in a TGF-β- like modality.

Concerning the connection between mesenchymal stem cells (MSC) and skin regeneration, recent studies suggest that these cells secrete cytokines and growth factors that are implicated in regeneration and wound healing. Primitive umbilical-cord-blood-derived MSCs are responsible for GDF11 secretion. In fibroblasts, GDF11 stimulates the secretion of extracellular matrix proteins, including collagen type I and III and fibronectin.

GDF11 treatment antagonizes TNF-α-induced inflammation in macrophages (Lee et al, 2019), and the administration of GDF11 appears to attenuate skin inflammation. Studies show that TNF-α–induced activation of the nuclear factor kappa B (NF-κB) signaling pathway, which is implicated in various inflammatory conditions, is limited by GDF11 treatment (Wang et al., 2019). It is known that macrophages are closely associated with inflammatory reactions, including psoriasis-like skin inflammation. Psoriasis is the typical reaction of skin that is infiltrated by specific immune cells implicated in inflammation, which result in the destruction of the outer layer of the skin. In psoriasiform mouse models, adding GDF11 reduced macrophage accumulation in the skin by decreasing inflammatory cell infiltration.

The role of activins in the process of skin repair was demonstrated through the regulation of skin properties and immune cell migration. Another recent study (Idkowiak et al., 2019)  looked at the effect of recombinant (sh)GDF11 in various skin cells, such as human epidermal dermal fibroblasts, keratinocytes, melanocytes, dermal microvascular endothelial cells, and 3D skin equivalents, as well as in ex vivo human skin explants. When the skin models were treated with physiologically relevant levels of shGDF11, researchers saw substantial changes in the production of hyaluronic acid and procollagen I. Enhancement of physiological GDF11 levels (via shGDF11 administration) led to increased collagen I and hyaluronic acid production in those models, along with reduced melanin, indicating potential benefits of GDF11 for skin biology.

In short, GDF11 induces protective effects in various tissues through the suppression of oxidative stress and the expression of HSPs; the AKT/Smad 2/3 pathways are also implicated in these events. As a key member of the TGF-β superfamily, shGDF11 is a promising therapeutic agent for treating a range of inflammatory skin diseases, including psoriasis.

Skin Active Proteins Rejuvenating Factor

What would you prefer to use on your skin to increase GDF-11? Umbilical cord blood (Kim et al 2028), plant extracts that may influence GDF-11 production, or the protein, pure, shown to be responsible for their benefits?

At Skin Active Proteins, we offer you protein that can be added to any formulation at the final, cool stage. Its INCI name is sh-Polypeptide-22, and it is classified as a skin protectant.

References

Idkowiak-Baldys J, Santhanam U, Buchanan SM, Pfaff KL, Rubin LL, Lyga J. (2019) Growth differentiation factor 11 (GDF11) has pronounced effects on skin biology. PLoS One. 2019; 14:e0218035. 10.1371/journal.pone.0218035.

Kim, Y.J.; Seo, D.H.; Lee, S.H.; Lee, S.H.; An, G.H.; Ahn, H.J.; Kwon, D.; Seo, K.W.; Kang, K.S. (2018) Conditioned media from human umbilical cord blood-derived mesenchymal stem cells stimulate rejuvenation function in human skin. Biochem. Biophys. Rep. 16: 96–102.

Li, W. ; Wang, W. ; Liu, L. ; Qu, R. ; Chen, X. ; Qiu, C. ; Li, J. ; Hayball, J. ; Liu, L. ; Chen, J. ; et al. (2019) GDF11 antagonizes TNF-alpha-induced inflammation and protects against the development of inflammatory arthritis in mice. FASEB J. 33: 3317–3329.

Ma Y, Liu Y, Han F, Qiu H, Shi J, Huang N, Hou N, Sun X. (2021) Growth differentiation factor 11: a “rejuvenation factor” involved in regulation of age-related diseases? Aging (Albany NY). 2021 Apr 22;13:12258-12272. doi: 10.18632/aging.202881. Epub 2021 Apr 22. PMID: 33886503; PMCID: PMC8109099.

Moura, J.; da Silva, L.; Cruz, M.T.; Carvalho, E. (2013) Molecular and cellular mechanisms of bone morphogenetic proteins and activins in the skin: Potential benefits for wound healing. Arch. Dermatol. Res. 305:557–569.

Rochette, L.; Mazini, L.; Meloux, A.; Zeller, M.; Cottin, Y.; Vergely, C.; Malka, G. (2020) Anti-Aging Effects of GDF11 on Skin. Int. J. Mol. Sci.  21, 2598. https://doi.org/10.3390/ijms21072598

Wang, W.; Qu, R.; Wang, X.; Zhang, M.; Zhang, Y.; Chen, C.; Chen, X.; Qiu, C.; Li, J.; Pan, X.; et al. (2019) GDF11 Antagonizes Psoriasis-like Skin Inflammation via Suppression of NF-kappaB Signaling Pathway. Inflammation 42: 319–330.