Feasibility of intravenous injection of pig plasma extracellular particles into rats: an acute study
Keywords:
Pig Plasma Extracellular Particles (PPEPs), Small extracellular vesicles, Blood, Sprague-Dawley rats, Injection, Histology, Immune reactionAbstract
Extracellular particles (EPs), especially small extracellular vesicles (EVs), extracted from young animals are increasingly being studied in animal models as agents for regeneration and rejuvenation, with studies using EPs from one species injected into another showing no immune reaction. In this study, we aimed to investigate if the injection of Pig Plasma Extracellular Particles (PPEPs) into rats would produce an acute immune or toxic reaction. Blood from a young pig was collected, PPEPs were isolated by size exclusion chromatography and injected into young male Sprague-Dawley rats, while the control group received a sterile saline injection. After 9 days, the animals were euthanized and their organs were histologically analyzed for signs of cellular damage or immune infiltration. The treated rats showed no signs of acute immunological reaction, behaving normally immediately after the injections and during the 9 days since the first injection. Throughout the trial period, the animals continued gaining weight normally and the histological analysis of their liver, kidney and spleen showed no signs of acute toxicity. PPEPs from young animals do not cause an acute immune or toxic response when injected intravenously into young male Sprague-Dawley rats.
References
1. Ural EE, Toomajian V, Hoque Apu E, Veletic M, Balasingham I, Ashammakhi N, et al. Visualizing Extracellular Vesicles and Their Function in 3D Tumor Microenvironment Models. Int J Mol Sci. 2021; 22(9): 4784.
2. Welsh JA, Goberdhan DCI, O’Driscoll L, Buzas EI, Blenkiron C, Bussolati B, et al. Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. J Extracell Vesicles. 2024; 13(2): e12404.
3. Mori MA, Ludwig RG, Garcia-Martin R, Brandão BB, Kahn CR. Extracellular miRNAs: From Biomarkers to Mediators of Physiology and Disease. Cell Metab. 2019; 30(4): 656-673.
4. Lananna B V, Imai SI. Friends and foes: Extracellular vesicles in aging and rejuvenation. FASEB Bioadv. 2021; 3(10): 787-801.
5. Kourembanas S. Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu Rev Physiol. 2015; 77: 13-27.
6. Robbins PD. Extracellular vesicles and aging. Stem Cell Investig. 2017; 4(12): 98-98.
7. Prattichizzo F, Giuliani A, Sabbatinelli J, Mensà E, De Nigris V, La Sala L, et al. Extracellular vesicles circulating in young organisms promote healthy longevity. J Extracell Vesicles. 2019; 8(1): 1656044.
8. Kim HY, Kwon S, Um W, Shin S, Kim CH, Park JH, et al. Functional Extracellular Vesicles for Regenerative Medicine. Small. 2022; 18(36): 2106569.
9. Boulestreau J, Maumus M, Rozier P, Jorgensen C, Noël D. Mesenchymal Stem Cell Derived Extracellular Vesicles in Aging. Front Cell Dev Biol. 2020; 8.
10. Sahu A, Clemens ZJ, Shinde SN, Sivakumar S, Pius A, Bhatia A, et al. Regulation of aged skeletal muscle regeneration by circulating extracellular vesicles. Nat Aging. 2021; 1(12): 1148-1161.
11. Fitz NF, Sahu A, Lu Y, Ambrosio F, Lefterov I, Koldamova R. Extracellular Vesicles in Young Serum Contribute to the Restoration of Age-Related Brain Transcriptomes and Cognition in Old Mice. Int J Mol Sci. 2023; 24(16): 12550.
12. Horvath S, Singh K, Raj K, Khairnar SI, Sanghavi A, Shrivastava A, et al. Reversal of biological age in multiple rat organs by young porcine plasma fraction. Geroscience. 2023; 46: 367-394.
13. Chen X, Luo Y, Zhu Q, Zhang J, Huang H, Kan Y, et al. Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism. Nat Aging. 2024; 4(6): 814-838.
14. Yu L, Wen H, Liu C, Wang C, Yu H, Zhang K, et al. Embryonic stem cell-derived extracellular vesicles rejuvenate senescent cells and antagonize aging in mice. Bioact Mater. 2023; 29: 85-97.
15. Li X, Zhang H, Wang X, Lu M, Ding Q, Chen AF, et al. iPSC-derived exosomes promote angiogenesis in naturally aged mice. Aging. 2023; 15(12): 5854-5872.
16. Dorronsoro A, Santiago FE, Grassi D, Zhang T, Lai RC, McGowan SJ, et al. Mesenchymal stem cell-derived extracellular vesicles reduce senescence and extend health span in mouse models of aging. Aging Cell. 2021; 20(4): e13337.
17. Grigorian Shamagian L, Rogers RG, Luther K, Angert D, Echavez A, Liu W, et al. Rejuvenating effects of young extracellular vesicles in aged rats and in cellular models of human senescence. Sci Rep. 2023; 13(1): 12240.
18. Bruno S, Tapparo M, Collino F, Chiabotto G, Deregibus MC, Soares Lindoso R, et al. Renal Regenerative Potential of Different Extracellular Vesicle Populations Derived from Bone Marrow Mesenchymal Stromal Cells. Tissue Eng Part A. 2017; 23(21-22): 1262-1273.
19. Sanz-Ros J, Huete-Acevedo J, Mas-Bargues C, Romero-García N, Dromant M, van Weeghel M, et al. Small extracellular vesicles from young adipose-derived stem cells ameliorate age-related changes in the heart of old mice. bioRxiv. 2024: 2024.06.06.597840.
20. Sanz-Ros J, Romero-García N, Mas-Bargues C, Monleón D, Gordevicius J, Brooke RT, et al. Small extracellular vesicles from young adipose-derived stem cells prevent frailty, improve health span, and decrease epigenetic age in old mice. Sci Adv. 2022; 8(42): eabq2226.
21. Torbjörn O. Amniotic derived exosomes in the treatment of degenerative bone- and cartilage disease: A case series. Open Journal of Orthopedics and Rheumatology; 2024; 9(1): 001-006.
22. Fafián-Labora JA, Rodríguez-Navarro JA, O’Loghlen A. Small Extracellular Vesicles Have GST Activity and Ameliorate Senescence-Related Tissue Damage. Cell Metab. 2020; 32(1): 71-86.e5.
23. Rao S, He Z, Wang Z, Yin H, Hu X, Tan Y, et al. Extracellular vesicles from human urine-derived stem cells delay aging through the transfer of PLAU and TIMP1. Acta Pharm Sin B. 2024; 14(3): 1166-1186.
24. Katcher H. The Illusion of Knowledge: The paradigm shift in aging research that shows the way to human rejuvenation. 1st edn, NTZ; 2021.
25. Cytiva Life Sciences. Instructions for Sephadex Media [Internet]. [cited 2024 Oct 15]. Available from: https://www.cytivalifesciences.co.jp/tech_support/manual/pdf/17000001.pdf
26. Thermo Scientific. User Guide: Disposable Plastic Columns [Internet]. 2011 [cited 2024 Oct 15]. Available from: https://assets.fishersci.com/TFS-Assets/LSG/manuals/MAN0011162_Disposable_Plastic_Column_UG.pdf
27. Lu AT, Fei Z, Haghani A, Robeck TR, Zoller JA, Li CZ, et al. Universal DNA methylation age across mammalian tissues. Nat Aging. 2023; 3(9): 1144-1166.
28. Katcher HL. Anecdotal Evidence Elucidates the Aging Process. Curr Aging Sci. 2024; 17(3): 175-179.
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