Growth differentiation factor 6 derived from mesenchymal stem/stromal cells reduces age-related functional deterioration in multiple tissues

Abstract

The senescence-associated secretory phenotype (SASP) has attracted attention as a mechanism that connects cellular senescence to tissue dysfunction, and specific SASP factors have been identified as systemic pro-aging factors. However, little is known about the age-dependent changes in the secretory properties of stem cells. Young, but not old, mesenchymal stem/stromal cells (MSCs) are a well-known source of critical regenerative factors, but the identity of these factors remains elusive. In this study, we identified growth differentiation factor 6 (Gdf6; also known as Bmp13 and CDMP-2) as a regenerative factor secreted from young MSCs. The expression of specific secretory factors, including Gdf6, was regulated by the microRNA (miRNA) miR-17, whose expression declined with age. Upregulation of Gdf6 restored the osteogenic capacity of old MSCs in vitro and exerted positive effects in vivo on aging-associated pathologies such as reduced lymphopoiesis, insufficient muscle repair, reduced numbers of neural progenitors in the brain, and chronic inflammation. Our results suggest that manipulation of miRNA could enable control of the SASP, and that regenerative factors derived from certain types of young cells could be used to treat geriatric diseases.

c-Kit modifies the inflammatory status of smooth muscle cells

“…We also show decreased expression of the anti-inflammatory genes Foxo1 , Gdf6 , Igf1 , Igf2r , and Lpl (Ziouzenkova et al, 2003; Sukhanov et al, 2007; Savai et al, 2014; Hisamatsu et al, 2016). Lipoprotein lipase ( Lpl ), for example, is 14-fold lower in c-Kit deficient cells than in those isolated from littermate controls.…”

Therapeutic potential of growth differentiation factors in the treatment of degenerative disc diseases

“…Meanwhile, IL‐1β and TNF‐α were both found to downregulate GDF5 expression significantly in human AF cells in 3D culture . In a mouse model, plasma levels of inflammatory factors were downregulated by overexpression of human GDF6 . This indicates an indirect role in the decrease of catabolic enzyme production linked to cellular response to proinflammatory cytokine signaling.…”

Microparticles for controlled growth differentiation factor 6 delivery to direct adipose stem cell‐based nucleus pulposus regeneration

“…One growth factor recently proposed for NP regeneration is growth differentiation factor 6 (GDF6), a member of the bone morphogenetic protein (BMP) family that plays important developmental roles in the formation of cartilaginous tissues, including the IVD (Clendenning & Mortlock, 2012;Settle et al, 2003;Tassabehji et al, 2008;Wei et al, 2016). GDF6 expression has been linked to anti-ageing effects in multiple tissues (Hisamatsu, Ohno-Oishi, Nakamura, Mabuchi, & Naka-Kaneda, 2016) and, whereas studies conducted in our laboratory and others do not suggest GDF6 expression decreases with degeneration (Gulati, Chung, Wei, & Diwan, 2015; Le Maitre, Freemont, & Hoyland, 2009), preclinical studies have demonstrated that injection of GDF6 into experimentally induced rabbit and ovine annular puncture models attenuates pro-inflammatory molecular changes and prevents progression of IVD degeneration (Miyazaki et al, 2018;Shen et al, 2009). However, the hypocellular nature of the tissue and the aberrant phenotype of degenerate NP cells suggests that growth factor therapy alone may be insufficient to promote regeneration of human IVD.…”