Limb regeneration: what are the problems/knowledge gaps that need to be solved?
Image credit: James Monaghan laboratory/Northeastern University
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Is the problem still unsolved?
Is it concisely described?
- Tissue engineering - using stem cells and biomaterials to rebuild a lost limb
- Harnessing endogenous regenerative potential
1. Fakorede, F. A. (2018). "Increasing awareness about peripheral artery disease can save limbs and lives." Am J Manag Care 24 (14 Spec No.): SP609.
What is the process in which the cells used to make the blastema dedifferentiate and then become differentiated once again?
- How can these animals switch from differentiated cells to dedifferentiated cells, and then back to differentiated cells again?
- Are there any more miRNAs involved in limb regeneration specifically?
- Which genes do these specific miRNAs target?
Abo‐Al‐Ela, Haitham G., and Mario A. Burgos‐Aceves. "Exploring the role of microRNAs in axolotl regeneration." Journal of Cellular Physiology (2020).
King, Benjamin L., and Viravuth P. Yin. "A conserved microRNA regulatory circuit is differentially controlled during limb/appendage regeneration." PLoS One 11.6 (2016): e0157106.
Holman, Edna C., et al. "Microarray analysis of microRNA expression during axolotl limb regeneration." PLoS One 7.9 (2012): e41804.
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Challenges limitations and a possible strategy to Endogenous tissues regeneration
- The immune system
- The embryonic program activation
- 80% hydration
- hyaluronate content of at least 30–40 ug/mg dry weight, similar to that of the umbilical cord (60–80 ug/mg dry weight). This concentration of hyaluronate is over 100–300 times higher than in average human tissues (0.2–0.3 g/mg dry weight). For an average human weighing 70kg, it would be 15g total. The formation of large and soft outgrowths rich in hyaluronate and water may therefore be the key to promote limb regeneration in humans, but the size of these outgrowths is a problem (9).
- Deers regrow their antlers without scarring, however in this case no blastema structures form. But it is stem cells mediated
- There is a mouse model with a remarkable ear tissue regeneration – without scarring – after ear punch. In this case, a blastema-like structure is observed. Could it be a valid model? -
- The CD1 mouse can I even regrow bone after amputation and it has been used as a model to investigate limb regeneration.
- The size of the limb portion to regenerate
- The time it will take
- The fine balance between growth factors to avoid triggering cancer-like behaviour
- The limitation of humanized models References: 1- Toole, B.P. (1997), Hyaluronan in morphogenesis. Journal of Internal Medicine, 242: 35-40. doi:10.1046/j.1365-2796.1997.00171.x 2- Stocum D.L. (2013) Urodele Limb Regeneration: Mechanisms of Blastema Formation and Growth. In: Sell S. (eds) Stem Cells Handbook. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-7696-2_7 3- Blastema: https://en.wikipedia.org/wiki/Blastema 4- Vitulo, N., Dalla Valle, L., Skobo, T., Valle, G., Alibardi, L., 2017b. Down-regulation of lizard immuno-genes in the regenerating tail and myo-genes in the scarring limb suggests that tail regeneration occurs in an immune-privileged organ. Protoplasma 254, 2127–2141, http://dx.doi.org/10.1007/s00709-107-1107-y. 5- Aurora, A. B., & Olson, E. N. (2014). Immune modulation of stem cells and regeneration. Cell stem cell, 15(1), 14–25. https://doi.org/10.1016/j.stem.2014.06.009 6- Gabrilovich, D., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12, 253–268 (2012). https://doi.org/10.1038/nri3175 7- Atala A, Irvine DJ, Moses M, Shaunak S. Wound Healing Versus Regeneration: Role of the Tissue Environment in Regenerative Medicine. MRS Bull. 2010;35(8):10.1557/mrs2010.528. doi:10.1557/mrs2010.528 8- Litwiniuk M, Krejner A, Speyrer MS, Gauto AR, Grzela T. Hyaluronic Acid in Inflammation and Tissue Regeneration. Wounds. 2016;28(3):78-88. 9- Lorenzo Alibardi, Review: Limb regeneration in humans: Dream or reality? 2018, https://doi.org/10.1016/j.aanat.2017.12.008. 10- Seifert AW, Muneoka K. The blastema and epimorphic regeneration in mammals. Dev Biol. 2018;433(2):190-199. doi:10.1016/j.ydbio.2017.08.007 11-Simkin J, Sammarco MC, Marrero L, et al. Macrophages are required to coordinate mouse digit tip regeneration. Development. 2017;144(21):3907-3916. doi:10.1242/dev.150086 12- Simkin J, Sammarco MC, Dawson LA, Schanes PP, Yu L, Muneoka K. The mammalian blastema: regeneration at our fingertips. Regeneration (Oxf). 2015;2(3):93-105. Published 2015 Jun 9. doi:10.1002/reg2.36 13- Julien Barthes, 2014 Cell/Tissue Microenvironment Engineering and Monitoring in Tissue Engineering, Regenerative Medicine, and In Vitro Tissue Models