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Neuropeptide Y Promotes the Treatment of Adipose Stem Cells on Type 2 Diabetic Wounds

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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Background:

Type 2 diabetes (T2D) is a common metabolic disorder. Due to insufficient insulin secretion or insulin resistance, increased blood glucose often leads to impaired wound healing in T2D patients. Our previous research showed that adipose-derived stem cells (ASCs) from normal mice and T2D mice improved the cutaneous wound healing of diabetic mice. We also found that the expression of neuropeptide Y (NPY) in T2D ASCs was significantly decreased.

Methods:

In order to explore the effects of NPY on ASCs and diabetic wound healing, we investigated the effects of NPY on ASCs proliferation and growth factors expression and secretion, the effects of NPY on skin fibroblasts, and the effects of NPY combined with ASCs on T2D wound healing.

Results:

The results showed that a certain concentration of NPY could promote the proliferation and the growth factors expression and secretion of ASCs, and promote the proliferation and migration of fibroblasts. At the same time, NPY and ASCs have a synergistic effect, which can promote wound healing and decrease inflammation in T2D wounds. NPY may regulate ASCs through the ERK pathway. These results are conducive to promoting ASCs and NPY in the treatment of diabetic wounds.

Conclusions:

NPY can promote the effect of ASCs in the treatment of diabetic wounds.

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References

  1. Wang M, Song L, Strange C, Dong X, Wang H. Therapeutic effects of adipose stem cells from diabetic mice for the treatment of type 2 diabetes. Mol Ther. 2018;26:1921–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sun Y, Song L, Zhang Y, Wang H, Dong X. Adipose stem cells from type 2 diabetic mice exhibit therapeutic potential in wound healing. Stem Cell Res Ther. 2020;11:298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Li J, Wei M, Liu X, Xiao S, Cai Y, Li F, et al. The progress, prospects, and challenges of the use of non-coding RNA for diabetic wounds. Mol Ther Nucleic Acids. 2021;24:554–78.

  4. Kato Y, Iwata T, Morikawa S, Yamato M, Okano T, Uchigata Y. Allogeneic transplantation of an adipose-derived stem cell sheet combined with artificial skin accelerates wound healing in a rat wound model of type 2 diabetes and obesity. Diabetes. 2015;64:2723–34.

  5. Marfia G, Navone SE, Di Vito C, Ughi N, Tabano S, Miozzo M, et al. Mesenchymal stem cells: potential for therapy and treatment of chronic non-healing skin wounds. Organogenesis. 2015;11:183–206.

  6. Zhu D, Chen L, Hong T, Chinese Diabetes S. Position statement of the Chinese diabetes society regarding stem cell therapy for diabetes. J Diabetes. 2012;4:18–21.

  7. An R, Zhang Y, Qiao Y, Song L, Wang H, Dong X. Adipose stem cells isolated from diabetic mice improve cutaneous wound healing in streptozotocin-induced diabetic mice. Stem Cell Res Ther. 2020;11:120.

  8. Shen L, Zeng W, Wu YX, Hou CL, Chen W, Yang MC, Li L, Zhang YF, Zhu CH. Neurotrophin-3 accelerates wound healing in diabetic mice by promoting a paracrine response in mesenchymal stem cells. Cell Transplant. 2013;22:1011–21.

  9. Zhao X, Zhang Y, Zuo X, Wang S, Dong X. Knockdown of Adra2a increases secretion of growth factors and wound healing ability in diabetic adipose-derived stem cells. Stem Cells Int. 2022;2022:5704628.

  10. Tatemoto K, Carlquist M, Mutt V. Neuropeptide Y–a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide. Nature. 1982;296:659–60.

  11. Jen PY, Li WW, Yew DT. Immunohistochemical localization of neuropeptide y and somatostatin in human fetal retina. Neuroscience. 1994;60:727–35.

  12. Baldock PA, Allison SJ, Lundberg P, Lee NJ, Slack K, Lin EJ, et al. Novel role of Y1 receptors in the coordinated regulation of bone and energy homeostasis. J Biol Chem. 2007;282:19092–102.

  13. Yang K, Guan H, Arany E, Hill DJ, Cao X. Neuropeptide Y is produced in visceral adipose tissue and promotes proliferation of adipocyte precursor cells via the Y1 receptor. FASEB J. 2008;22:2452–64.

  14. Cavadas C, Silva AP, Mosimann F, Cotrim MD, Ribeiro CA, Brunner HR. NPY regulates catecholamine secretion from human adrenal chromaffin cells. J Clin Endocrinol Metab. 2001;86:5956–63.

  15. Myers AK, Farhat MY, Vaz CA, Keiser HR, Zukowska-Grojec Z. Release of immunoreactive-neuropeptide Y by rat platelets. Biochem Biophys Res Commun. 1988;155:118–22.

  16. Kalra SP, Dube MG, Sahu A, Phelps CP, Kalra PS. Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. Proc Natl Acad Sci U S A. 1991;88:10931–5.

  17. Sindelar DK, Palmiter RD, Woods SC, Schwartz MW. Attenuated feeding responses to circadian and palatability cues in mice lacking neuropeptide Y. Peptides. 2005;26:2597–602.

  18. Nguyen AD, Herzog H, Sainsbury A. Neuropeptide Y and peptide YY: important regulators of energy metabolism. Curr Opin Endocrinol Diabetes Obes. 2011;18:56–60.

  19. Magni P. Hormonal control of the neuropeptide Y system. Curr Protein Pept Sci. 2003;4:45–57.

  20. Jacques D, Abdel-Samad D. Neuropeptide Y (NPY) and NPY receptors in the cardiovascular system: implication in the regulation of intracellular calcium. Can J Physiol Pharmacol. 2007;85:43–53.

  21. Wu JQ, Jiang N, Yu B. Mechanisms of action of neuropeptide Y on stem cells and its potential applications in orthopaedic disorders. World J Stem Cells. 2020;12:986–1000.

  22. Igura K, Haider H, Ahmed RP, Sheriff S, Ashraf M. Neuropeptide y and neuropeptide y y5 receptor interaction restores impaired growth potential of aging bone marrow stromal cells. Rejuvenation Res. 2011;14:393–403.

  23. Wu W, Hu P, Liang F, Song X, Liu M. High-dose neuropeptide Y inhibits proliferation and promotes differentiation of human adipose-derived stem cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2016;32:185–90.

    PubMed  Google Scholar 

  24. Wu J, Liu S, Meng H, Qu T, Fu S, Wang Z, Yang J, Jin D, Yu B. Neuropeptide Y enhances proliferation and prevents apoptosis in rat bone marrow stromal cells in association with activation of the Wnt/beta-catenin pathway in vitro. Stem Cell Res. 2017;21:74–84.

    Article  CAS  PubMed  Google Scholar 

  25. Buttari B, Profumo E, Darcangelo D, Di Raimo T, Businaro R, Capoano R, et al. Neuropeptide Y as regulator of macrophage phenotype and functions: a neuroimmune CUE in atherosclerosis regression? Atherosclerosis. 2017;263:e2.

    Article  Google Scholar 

  26. Theocharidis G, Veves A. Autonomic nerve dysfunction and impaired diabetic wound healing: the role of neuropeptides. Auton Neurosci. 2020;223:102610.

  27. Wheway J, Herzog H, Mackay F. NPY and receptors in immune and inflammatory diseases. Curr Top Med Chem. 2007;7:1743–52.

  28. Pradhan L, Nabzdyk C, Andersen ND, LoGerfo FW, Veves A. Inflammation and neuropeptides: the connection in diabetic wound healing. Expert Rev Mol Med. 2009;11:e2.

  29. Ericsson A, Schalling M, McIntyre KR, Lundberg JM, Larhammar D, Seroogy K, et al. Detection of neuropeptide Y and its mRNA in megakaryocytes: enhanced levels in certain autoimmune mice. Proc Natl Acad Sci U S A. 1987;84:5585–9.

  30. Ahlborg G, Lundberg JM. Exercise-induced changes in neuropeptide Y, noradrenaline and endothelin-1 levels in young people with type I diabetes. Clin Physiol. 1996;16:645–55.

  31. Wallengren J, Badendick K, Sundler F, Hakanson R, Zander E. Innervation of the skin of the forearm in diabetic patients: relation to nerve function. Acta Derm Venereol. 1995;75:37–42.

  32. Levy DM, Karanth SS, Springall DR, Polak JM. Depletion of cutaneous nerves and neuropeptides in diabetes mellitus: an immunocytochemical study. Diabetologia. 1989;32:427–33.

  33. Kuncova J, Sviglerova J, Tonar Z, Slavikova J. Heterogenous changes in neuropeptide Y, norepinephrine and epinephrine concentrations in the hearts of diabetic rats. Auton Neurosci. 2005;121:7–15.

  34. Ilhan A, Rasul S, Dimitrov A, Handisurya A, Gartner W, Baumgartner-Parzer S, et al. Plasma neuropeptide Y levels differ in distinct diabetic conditions. Neuropeptides. 2010;44:485–9.

  35. Kos K, Harte AL, James S, Snead DR, O’Hare JP, McTernan PG, et al. Secretion of neuropeptide Y in human adipose tissue and its role in maintenance of adipose tissue mass. Am J Physiol Endocrinol Metab. 2007;293:E1335–40.

  36. Howell OW, Scharfman HE, Herzog H, Sundstrom LE, Beck-Sickinger A, Gray WP. Neuropeptide Y is neuroproliferative for post-natal hippocampal precursor cells. J Neurochem. 2003;86:646–59.

  37. Movafagh S, Hobson JP, Spiegel S, Kleinman HK, Zukowska Z. Neuropeptide Y induces migration, proliferation, and tube formation of endothelial cells bimodally via Y1, Y2, and Y5 receptors. FASEB J. 2006;20:1924–6.

  38. Panuccio V, Cutrupi S, Pizzini P, Mallamaci F, Tripepi G, Zoccali C. Neuropeptide Y and markers of osteoblast activity in dialysis patients: a cross-sectional study. Am J Kidney Dis. 2007;50:1001–8.

  39. Wang Y, Zhang D, Ashraf M, Zhao T, Huang W, Ashraf A, et al. Combining neuropeptide Y and mesenchymal stem cells reverses remodeling after myocardial infarction. Am J Physiol Heart Circ Physiol. 2010;298:H275–86.

  40. Marion-Audibert AM, Nejjari M, Pourreyron C, Anderson W, Gouysse G, Jacquier MF, et al. Effects of endocrine peptides on proliferation, migration and differentiation of human endothelial cells. Gastroenterol Clin Biol. 2000;24:644–8.

  41. Zukowska-Grojec Z, Karwatowska-Prokopczuk E, Rose W, Rone J, Movafagh S, Ji H, et al. Neuropeptide Y: a novel angiogenic factor from the sympathetic nerves and endothelium. Circ Res. 1998;83:187–95.

  42. Businaro R, Scaccia E, Bordin A, Pagano F, Corsi M, Siciliano C, et al. Platelet lysate-derived neuropeptide y influences migration and angiogenesis of human adipose tissue-derived stromal cells. Sci Rep. 2018;8:14365.

  43. Cheung A, Newland PL, Zaben M, Attard GS, Gray WP. Intracellular nitric oxide mediates neuroproliferative effect of neuropeptide y on postnatal hippocampal precursor cells. J Biol Chem. 2012;287:20187–96.

  44. Peng S, Zhou YL, Song ZY, Lin S. Effects of neuropeptide Y on stem cells and their potential applications in disease therapy. Stem Cells Int. 2017;2017:6823917.

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Acknowledgement

This work was supported by the Natural Science Foundation of Shandong Province, China (ZR2022MC112).

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Author notes

  1. Tinghuan Lu, Lu Cong and Tong Jiang have contributed equally to this project and should be considered as first authors.

Authors and Affiliations

  1. College of Life Science, Qingdao Agricultural University, No. 700, Changcheng Road, Chengyang District, Qingdao, 266109, Shandong, People’s Republic of China

    Tinghuan Lu, Tong Jiang, Xiao Dong & Lili Song

  2. Department of Neurology, Peking University People’s Hospital, Beijing, 100044, People’s Republic of China

    Lu Cong

  3. School of Life Science, Shandong University, No. 72, Binhai Road, Qingdao, 266237, Shandong, People’s Republic of China

    Lili Song

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  1. Tinghuan Lu
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  2. Lu Cong
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  4. Xiao Dong
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Contributions

LS, XD, and TL conceived and designed research; LS, TL, LC, and TJ performed experiments; LS, and TL prepared figures; XD drafted manuscript. LS, XD, TL, LC, and TJ approved final manuscript.

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Correspondence to Xiao Dong or Lili Song.

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Ethical statement

The study was approved by the Institutional Animal Care and Use Committee at Qingdao Agricultural University University (IACUC no. SYXK 2022 0021).

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Lu, T., Cong, L., Jiang, T. et al. Neuropeptide Y Promotes the Treatment of Adipose Stem Cells on Type 2 Diabetic Wounds. Tissue Eng Regen Med 20, 683–694 (2023). https://doi.org/10.1007/s13770-023-00540-1

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  • DOI: https://doi.org/10.1007/s13770-023-00540-1

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