In Molecular Therapy, researchers have described their creation of cells that express the regenerative factor GDF11 and found that they ameliorate fibrosis in a mouse model.
Context-dependent benefits
Like sirtuins and klotho, GDF11 is a biochemical factor that has been heavily investigated in the context of age-related diseases [1]. However, research on it has been contradictory, with some research finding that it is detrimental for muscle regeneration [2] and other research finding that it is beneficial [3]. Some research has found that GDF11 mitigates fibrosis [4], while other research has found that it causes it [5].
These researchers offer several explanations as to why. There are measurement problems involving its similarity to GDF8, but its effects are also extremely context-dependent, varying by dose, disease, fibrosis amount, and tissue type [6].
All of these caveats, along with GDF11’s high cost of manufacture and short half-life in the body, make using it as a drug extremely difficult. The proper dose at the right time may provide significant benefits, but improper dosing can be very dangerous [7].
Therefore, these researchers have developed an embryonic stem cell (ESC) line that endogenously produces GDF11 and can be triggered to secrete it. They differentiated lung progenitors from these engineered cells, which have been made safer with a kill switch that removes harmful cells that proliferate too rapidly [8].
Beneficial for lung cells
In their first experiment, the researchers confirmed that older mice express the Gdf11 gene much less than their younger counterparts. Interestingly, 12-month-old and 24-month-old mice do not differ much in this respect, and so 12-month-old mice were chosen as the “old” group in future experiments; the young mice they were compared to were only 8 to 10 weeks old.
Some of these mice were subjected to a lung injury that involes bleomycin, which induces fibrosis. This is a well-known model that mimics idiopathic pulmonary fibrosis (IPF) in human beings. Unsurprisingly, the older mice could not recover from fibrosis 28 days after bleomycin exposure in the same way that the young mice did.
This injury decreased Gdf11 exposure in the old mice compared to healthy age-matched controls. The researchers also discovered a negative association between Gdf11 and the fibrosis gene S100a4, a gene that was accompanied by an increase in the senescence-related gene p16.
The researchers then returned to cells, examining alveolar type II cells (AEC-IIs) that reside in the distal lung. Exposing old AEC-11s to recombinant GDF11 restored their expression of surfactant protein C, which is vital for these cells’ function, and restored mitochondrial function as well, reducing the effects of oxidative stress.
The telomeres of these AEC-11s were lengthened by GDF11 as well, and there were no effects in this respect on young cells. DNA damage appeare to be reduced, and senescence genes were reduced as well. This was accomplished without killing the senescent cells, making GDF11 a senomorphic compound rather than a senolytic one for these cells.
Then, the researchers further described the cells they had created for this study. They made sure that these particular cells were committed to being lung progenitors and that they would only produce GDF11 when prompted to do so by the administration of doxycycline, a drug that does not occur in nature. These cells were designated as SC-GDF11 cells.
The researchers then compared what happens to bleomycin-injured lung cells in the presence of either recombinant GDF11 or SC-GDF11 cells and doxycycline, along with other groups cultured alongside other cells that did not express GDF11. Compared to those groups, the GDF11-exposed cells fared much better, with significantly reduced signs of cellular senescence; the SC-GDF11 cells were even more effective than the recombinant GDF11.
Significantly reduced fibrosis in mice
Finally, the researchers tested their cells in older mice. Two weeks after bleomycin administration, they administered SC-GDF11 cells to one population, alongside a group that received cells that do not express GDF-11 along with a bleomycin-only group and a control group with uninjured lungs. The lungs of the SC-GDF11-treated mice looked much more like those of the control group compared to the non-GDF11 groups, with normal alveola and lung density along with far less fibrosis. The treatment group’s lungs were also able to inhale normal amounts of air, demonstrating a preservation of function.
These findings were confirmed with a gene expression analysis. Not only was Gdf11 restored, a variety of key senescence markers, including those responsible for the senescence-associated secretory phenotype (SASP), were significantly reduced, with some markers at the levels of the control group and others only slightly above it.
In total, these are strong results that suggest that this is a potential treatment. Of course, this is still only a murine and cellular study, the created cells were made for mice rather than human beings, and bleomycin-induced injury is still only a model of IPF. There is also a question of immune rejection; although the researchers have a potential remedy to this problem [9], it was not implemented in this particular study. Therefore, further work on designing cells for human use must be done before clinical trials can begin.
Literature
[1] Zhang, Y., Wei, Y., Liu, D., Liu, F., Li, X., Pan, L., … & Chen, D. (2017). Role of growth differentiation factor 11 in development, physiology and disease. Oncotarget, 8(46), 81604.
[2] Egerman, M. A., Cadena, S. M., Gilbert, J. A., Meyer, A., Nelson, H. N., Swalley, S. E., … & Glass, D. J. (2015). GDF11 increases with age and inhibits skeletal muscle regeneration. Cell metabolism, 22(1), 164-174.
[3] Sinha, M., Jang, Y. C., Oh, J., Khong, D., Wu, E. Y., Manohar, R., … & Wagers, A. J. (2014). Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science, 344(6184), 649-652.
[4] Dai, Z., Song, G., Balakrishnan, A., Yang, T., Yuan, Q., Möbus, S., … & Sharma, A. D. (2020). Growth differentiation factor 11 attenuates liver fibrosis via expansion of liver progenitor cells. Gut, 69(6), 1104-1115.
[5] Pons, M., Koniaris, L. G., Moe, S. M., Gutierrez, J. C., Esquela-Kerscher, A., & Zimmers, T. A. (2018). GDF11 induces kidney fibrosis, renal cell epithelial-to-mesenchymal transition, and kidney dysfunction and failure. Surgery, 164(2), 262-273.
[6] Zhang, F., Yang, X., & Bao, Z. (2022). Bioinformatics network analyses of growth differentiation factor 11. Open Life Sciences, 17(1), 426-437.
[7] Sutherland, B. A., Hadley, G., Alexopoulou, Z., Lodge, T. A., Neuhaus, A. A., Couch, Y., … & Buchan, A. M. (2020). Growth differentiation factor-11 causes neurotoxicity during ischemia in vitro. Frontiers in Neurology, 11, 1023.
[8] Liang, Q., Monetti, C., Shutova, M. V., Neely, E. J., Hacibekiroglu, S., Yang, H., … & Nagy, A. (2018). Linking a cell-division gene and a suicide gene to define and improve cell therapy safety. Nature, 563(7733), 701-704.
[9] Pavan, C., Davidson, K. C., Payne, N., Frausin, S., Hunt, C. P., Moriarty, N., … & Parish, C. L. (2025). A cloaked human stem-cell-derived neural graft capable of functional integration and immune evasion in rodent models. Cell Stem Cell, 32(5), 710-726.
View the article at lifespan.io
