Potential Utilisation of Secretome from Ascorbic Acid-Supplemented Stem Cells in Combating Skin Aging: Systematic Review of A Novel Idea

Document Type : Systematic Review

Authors

1 Doctoral Program, Faculty of Medicine, Universitas Udayana, Denpasar, Indonesia

2 Histology Department, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia

Abstract

The secretome of stem cells consists of a spectrum of bioactive factors secreted by stem cells grown in culture mediacytokines,
chemokines, and growth factors in addition to extracellular vesicles (exosomes and microvesicles). Ease
of handling and storage of secretomes along with their bioactivity towards processes in skin aging and customizability
makes them an appealing prospective therapy for skin aging. This systematic review aims to investigate the potential
usage of ascorbic acid (AA)-supplemented stem cell secretomes (SCS) in managing skin aging. We extracted articles
from three databases: PubMed, Scopus, and Cochrane. This review includes in vitro, in vivo, and clinical studies
published in English that discuss the correlation of AA-supplemented-SCS with skin aging. We identified 1111 articles
from database and non-database sources from which nine studies met the inclusion criteria. However, the study
results were less specific due to the limited amount of available research that specifically assessed the effects of AAsupplemented
SCS in skin aging. Although further studies are necessary, the AA modification of SCS is a promising
potential for improving skin health.

Keywords

Main Subjects


  1. Kumar LP, Kandoi S, Misra R, Vijayalakshmi S, Rajagopal K, Verma RS. The mesenchymal stem cell secretome: A new paradigm towards cell-free therapeutic mode in regenerative medicine. Cytokine Growth Factor Rev. 2019; 46: 1-9.
  2. González-González A, García-Sánchez D, Dotta M, Rodríguez- Rey JC, Pérez-Campo FM. Mesenchymal stem cells secretome: the cornerstone of cell-free regenerative medicine. World J Stem Cells. 2020; 12(12): 1529-1552.
  3. Konala VB, Mamidi MK, Bhonde R, Das AK, Pochampally R, Pal R. The current landscape of the mesenchymal stromal cell secretome: a new paradigm for cell-free regeneration. Cytotherapy. 2016; 18(1): 13-24.
  4. Zhang S, Duan E. Fighting against skin aging: the way from bench to bedside. Cell Transplant. 2018; 27(5): 729-738.
  5. Damayanti RH, Rusdiana T, Wathoni N. Mesenchymal stem cell secretome for dermatology application: a review. Clin Cosmet Investig Dermatol. 2021; 14: 1401-1412.
  6. Wang T, Guo S, Liu X, Xv N, Zhang S. Protective effects of adipose- derived stem cells secretome on human dermal fibroblasts from ageing damages. Int J Clin Exp Pathol. 2015; 8(12): 15739- 15748.
  7. Kerscher M, Wagner-Schiffler S, Noah EM, Fischer T, Greiner- Krüger D, Sattler S, et al. Cell-free blood cell secretome (BCS) counteracts skin aging: multi-center prospective regenerative aesthetic medicine study using Exokine®. Clin Cosmet Investig Dermatol. 2022; 15: 1157-1173.
  8. Hussein MAA, Hussein HAM, Thabet AA, Selim KM, Dawood MA, El-Adly AM, et al. Human wharton’s jelly mesenchymal stem cells secretome inhibits human SARS-CoV-2 and avian infectious bronchitis coronaviruses. Cells. 2022; 11(9): 1408.
  9. Mendes-Pinheiro B, Anjo SI, Manadas B, Da Silva JD, Marote A, Behie LA, et al. Bone marrow mesenchymal stem cells’ secretome exerts neuroprotective effects in a parkinson’s disease rat model. Front Bioeng Biotechnol. 2019; 7: 294.
  10. Fujisawa K, Hara K, Takami T, Okada S, Matsumoto T, Yamamoto N, et al. Evaluation of the effects of ascorbic acid on metabolism of human mesenchymal stem cells. Stem Cell Res Ther. 2018; 9(1): 93.
  11. Wahyuningsih KA, Karina K, Rosadi I, Rosliana I, Subroto WR. Effect of ascorbic acid on morphology of post-thawed human adipose- derived stem cells. Stem Cell Investig. 2020; 7: 16.
  12. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021; 372: n71.
  13. Wahyuningsih KA, Pangkahila W, Weta IW, Widiana IGR, Wahyuniari IAI. Systematic review of potential utilization of secretome from ascorbic acid-supplemented stem cells for skin aging. 2023. Available from: https://osf.io/7vjek/ doi: 10.17605/OSF.IO/8S9N7 (6 Jun 2023).
  14. Wei F, Qu C, Song T, Ding G, Fan Z, Liu D, et al. Vitamin C treatment promotes mesenchymal stem cell sheet formation and tissue regeneration by elevating telomerase activity. J Cell Physiol. 2012; 227(9): 3216-3224.
  15. Lui PP, Wong OT, Lee YW. Transplantation of tendon-derived stem cells pre-treated with connective tissue growth factor and ascorbic acid in vitro promoted better tendon repair in a patellar tendon window injury rat model. Cytotherapy. 2016; 18(1): 99-112.
  16. Diomede F, Marconi GD, Serroni M, Pizzicannella G, Trubiani O, Pizzicannella J. Ascorbic acid enhances bone parameter expression in human gingival mesenchymal stem cells. J Biol Regul Homeost Agents. 2019; 33(6): 1715-1723.
  17. Diomede F, Marconi GD, Guarnieri S, D’Attilio M, Cavalcanti MFXB, Mariggiò MA, et al. A Novel role of ascorbic acid in anti-inflammatory pathway and ROS generation in HEMA treated dental pulp stem cells. Materials (Basel). 2019; 13(1): 130.
  18. Bhandi S, Alkahtani A, Mashyakhy M, Abumelha AS, Albar NHM, secretome and stemness of stem cells from human exfoliated deciduous tooth (SHEDs). J Pers Med. 2021; 11(7): 589.
  19. Marconi GD, Fonticoli L, Guarnieri S, Cavalcanti MFXB, Franchi S, Gatta V, et al. Ascorbic acid: a new player of epigenetic regulation in LPS-gingivalis treated human periodontal ligament stem cells. Oxid Med Cell Longev. 2021; 2021: 6679708.
  20. Pizzicannella J, Marconi GD, Guarnieri S, Fonticoli L, Della Rocca Y, Konstantinidou F, et al. Role of ascorbic acid in the regulation of epigenetic processes induced by Porphyromonas gingivalis in endothelial-committed oral stem cells. Histochem Cell Biol. 2021; 156(5): 423-436.
  21. Pranskunas M, Šimoliūnas E, Alksne M, Martin V, Gomes PS, Puisys A, et al. Assessment of the bone healing process mediated by periosteum-derived mesenchymal stem cells’ secretome and a xenogenic bioceramic-an in vivo study in the rabbit critical size calvarial defect model. Materials (Basel). 2021; 14(13): 3512.
  22. Bacakova L, Zarubova J, Travnickova M, Musilkova J, Pajorova J, Slepicka P, et al. Stem cells: their source, potency and use in regenerative therapies with focus on adipose-derived stem cells – a review. Biotechnol Adv. 2018; 36(4): 1111-1126.
  23. Sandonà M, Di Pietro L, Esposito F, Ventura A, Silini AR, Parolini O, et al. Mesenchymal stromal cells and their secretome: new therapeutic perspectives for skeletal muscle regeneration. Front Bioeng Biotechnol. 2021; 9: 652970.
  24. Ahangar P, Mills SJ, Cowin AJ. Mesenchymal stem cell secretome as an emerging cell-free alternative for improving wound repair. Int J Mol Sci. 2020; 21(19): 7038.
  25. Sriramulu S, Banerjee A, Di Liddo R, Jothimani G, Gopinath M, Murugesan R, et al. Concise review on clinical applications of conditioned medium derived from human umbilical cord-mesenchymal stem cells (UC-MSCs). Int J Hematol Oncol Stem Cell Res. 2018; 12(3): 230-234.
  26. Sjerobabski-Masnec I, Situm M. Skin aging. Acta Clin Croat. 2010; 49(4): 515-518.
  27. Wong QYA, Chew FT. Defining skin aging and its risk factors: a systematic review and meta-analysis. Sci Rep. 2021; 11(1): 22075.
  28. Bonta M, Daina L, Muţiu G. The process of ageing reflected by histological changes in the skin. Rom J Morphol Embryol. 2013; 54 Suppl 3: 797-804.
  29. Lee H, Hong Y, Kim M. Structural and functional changes and possible molecular mechanisms in aged skin. Int J Mol Sci. 2021; 22(22): 12489.
  30. Rinnerthaler M, Bischof J, Streubel MK, Trost A, Richter K. Oxidative stress in aging human skin. Biomolecules. 2015; 5(2): 545-589.
  31. Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, et al. Oxidative stress: harms and benefits for human health. Oxid Med Cell Longev. 2017; 2017: 8416763.
  32. Wahyono P. Impact of Uv-b rays on photoaging. Int J Innov Eng

Res Technol. 2020; 7(6): 143-147.

  1. Han H, Liu Z, Yin J, Gao J, He L, Wang C, et al. D-galactose induces chronic oxidative stress and alters gut microbiota in weaned piglets. Front Physiol. 2021; 12: 634283.
  2. Wang Y, Wang L, Wen X, Hao D, Zhang N, He G, et al. NF-κB signaling in skin aging. Mech Ageing Dev. 2019; 184: 111160.
  3. García-García VA, Alameda JP, Page A, Casanova ML. Role of NF-κB in ageing and age-related diseases: lessons from genetically modified mouse models. Cells. 2021; 10(8): 1906.
  4. Rui Y, Zhaohui Z, Wenshan S, Bafang L, Hu H. Protective effect of MAAs extracted from Porphyra tenera against UV irradiation-induced photoaging in mouse skin. J Photochem Photobiol B. 2019; 192: 26-33.
  5. Li J, Yoshida Y, Kurita M, Usuki T. Cynaropicrin and inhibition of NF-κB activation: a structure activity relationship study. Bioorg Med Chem Lett. 2019; 29(12): 1518-1521.
  6. Lago JC, Puzzi MB. The effect of aging in primary human dermal fibroblasts. PLoS One. 2019; 14(7): e0219165.
  7. Al-Atif H. Collagen supplements for aging and wrinkles: a paradigm shift in the fields of dermatology and cosmetics. Dermatol Pract Concept. 2022; 12(1): e2022018.
  8. Slade D. Maneuvers on PCNA rings during DNA replication and repair. Genes (Basel). 2018; 9(8): 416.
  9. Salminen A, Kaarniranta K, Kauppinen A. Photoaging: UV radiation-induced inflammation and immunosuppression accelerate the aging process in the skin. Inflamm Res. 2022; 71(7-8): 817-831.
  10. Sergeyenko AM, Rosenfeld DJ, Tsoukas MM. Chronic immunosuppression in the mature patient. Clin Dermatol. 2018; 36(2): 255- 263.
  11. Csekes E, Račková L. Skin aging, cellular senescence and natural polyphenols. Int J Mol Sci. 2021; 22(23): 12641.
  12. Ho CY, Dreesen O. Faces of cellular senescence in skin aging. Mech Ageing Dev. 2021; 198: 111525.
  13. Jeong D, Qomaladewi NP, Lee J, Park SH, Cho JY. The role of autophagy in skin fibroblasts, keratinocytes, melanocytes, and epidermal stem cells. J Invest Dermatol. 2020; 140(9): 1691-1697.
  14. Eckhart L, Tschachler E, Gruber F. Autophagic control of skin aging. Front Cell Dev Biol. 2019; 7: 143.
  15. Mocchi M, Bari E, Marrubini G, Bonda AF, Perteghella S, Tartara F, et al. Freeze-dried mesenchymal stem cell-secretome pharmaceuticalization: optimization of formulation and manufacturing process robustness. Pharmaceutics. 2021; 13(8): 1129.
  16. Meiliana A, Dewi NM, Wijaya A. Mesenchymal stem cell secretome: cell-free therapeutic strategy in regenerative medicine. Indones Biomed J. 2019; 11(2): 113-124.
  17. Dalton CJ, Lemmon CA. Fibronectin: molecular structure, fibrillar structure and mechanochemical signaling. Cells. 2021; 10(9): 2443.
  18. Gimeno-LLuch I, Benito-Jardón M, Guerrero-Barberà G, Burday N, Costell M. The role of the fibronectin synergy site for skin wound healing. Cells. 2022; 11(13): 2100.
  19. Patten J, Wang K. Fibronectin in development and wound healing. Adv Drug Deliv Rev. 2021; 170: 353-368.
  20. Lukjanenko L, Jung MJ, Hegde N, Perruisseau-Carrier C, Migliavacca E, Rozo M, et al. Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle in mice. Nat Med. 2016; 22(8): 897-905.
  21. You J, Roh KB, Li Z, Liu G, Tang J, Shin S, et al. The antiaging properties of andrographis paniculata by activation epidermal cell stemness. Molecules. 2015; 20(9): 17557-17569
  22. Wahyuningsih KA. Effect of L-ascorbic acid-2-phosphate towards proliferation rate of human adipose-derived stem cells. Sapporo Med J. 2020; 54(7): 1-10.
  23. Panwar P, Hedtke T, Heinz A, Andrault PM, Hoehenwarter W, Granville DJ, et al. Expression of elastolytic cathepsins in human skin and their involvement in age-dependent elastin degradation. Biochim Biophys Acta Gen Subj. 2020; 1864(5): 129544.
  24. Langton AK, Hann M, Costello P, Halai P, Griffiths CEM, Sherratt MJ, et al. Remodelling of fibrillin-rich microfibrils by solar-simulated radiation: impact of skin ethnicity. Photochem Photobiol Sci. 2020; 19(9): 1160-1167.
  25. Sherratt MJ, Bayley CP, Reilly SM, Gibbs NK, Griffiths CE, Watson RE. Low-dose ultraviolet radiation selectively degrades chromophore- rich extracellular matrix components. J Pathol. 2010; 222(1): 32-40.
  26. Mellody KT. The intrinsic ageing of cutaneous fibrillin-rich microfibrils and the impact of photodamage upon their role as biosignalling molecules. Presented as Ph.D., Manchester. University of Manchester. 2019.
  27. Soydas T, Sayitoglu M, Sarac EY, Cınar S, Solakoglu S, Tiryaki T, et al. Metformin reverses the effects of high glucose on human dermal fibroblasts of aged skin via downregulating RELA/p65 expression. J Physiol Biochem. 2021; 77(3): 443-450.
  28. Yang M, Teng S, Ma C, Yu Y, Wang P, Yi C. Ascorbic acid inhibits senescence in mesenchymal stem cells through ROS and AKT/ mTOR signaling. Cytotechnology. 2018; 70(5): 1301-1313.
  29. Giacoppo S, Thangavelu SR, Diomede F, Bramanti P, Conti P, Trubiani O, et al. Anti-inflammatory effects of hypoxia-preconditioned human periodontal ligament cell secretome in an experimental model of multiple sclerosis: a key role of IL-37. FASEB J. 2017; 31(12): 5592-5608.
  30. Park KM, Yoo YJ, Ryu S, Lee SH. Nelumbo Nucifera leaf protects against UVB-induced wrinkle formation and loss of subcutaneous fat through suppression of MCP3, IL-6 and IL-8 expression. J Photochem Photobiol B. 2016; 161: 211-216.
  31. Miller-Kobisher B, Suárez-Vega DV, Velazco de Maldonado GJ. Epidermal growth factor in aesthetics and regenerative medicine: systematic review. J Cutan Aesthet Surg. 2021; 14(2): 137-146.
  32. de Araújo R, Lôbo M, Trindade K, Silva DF, Pereira N. Fibroblast growth factors: a controlling mechanism of skin aging. Skin Pharmacol Physiol. 2019; 32(5): 275-282. 65. Lu YE, Chen YJ. Resveratrol inhibits matrix metalloproteinase-1 and -3 expression by suppressing of p300/NFκB acetylation in TNF-α-treated human dermal fibroblasts. Chem Biol Interact. 2021; 337: 109395.
  33. Xie HF, Liu YZ, Du R, Wang B, Chen MT, Zhang YY, et al. miR-377 induces senescence in human skin fibroblasts by targeting DNA methyltransferase 1. Cell Death Dis. 2017; 8(3): e2663.
  34. Volarevic V, Markovic BS, Gazdic M, Volarevic A, Jovicic N, Arsenijevic N, et al. Ethical and safety issues of stem cell-based therapy. Int J Med Sci. 2018; 15(1): 36-45.
  35. Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard RE 2nd, et al. Vision loss after intravitreal injection of autologous “Stem Cells” for AMD. N Engl J Med. 2017; 376(11): 1047- 1053.
  36. Foo JB, Looi QH, Chong PP, Hassan NH, Yeo GEC, Ng CY, et al. Comparing the therapeutic potential of stem cells and their secretory products in regenerative medicine. Stem Cells Int. 2021; 2021: 2616807.
  37. Park YM, Lee M, Jeon S, Hrůzová D. In vitro effects of conditioned medium from bioreactor cultured human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on skin-derived cell lines. Regen Ther. 2021; 18: 281-291.
  38. Ogata K, Matsumura-Kawashima M, Moriyama M, Kawado T, Nakamura S. Dental pulp-derived stem cell-conditioned media attenuates secondary Sjögren’s syndrome via suppression of inflammatory cytokines in the submandibular glands. Regen Ther. 2021; 16: 73-80.
  39. Katagiri W, Osugi M, Kawai T, Hibi H. First-in-human study and clinical case reports of the alveolar bone regeneration with the secretome from human mesenchymal stem cells. Head Face Med. 2016; 12: 5.
  40. Putra A, Widyatmoko A, Ibrahim S, Amansyah F, Amansyah F, Berlian MA, et al. Case series of the first three severe COVID-19 patients treated with the secretome of hypoxia-mesenchymal stem cells in Indonesia. F1000Res. 2021; 10: 228.