Abstract
Chronic wounds continue to be a substantial public health concern contributing to both humanistic and economic burden worldwide. The magnitude of chronic wounds as a global healthcare crisis is likely to increase due to the rising geriatric and diabetic population, demanding novel therapeutic approaches that can restore the functionality of the skin at a reduced cost. Stem cell therapy has been widely acknowledged as a promising strategy for the repair of damaged tissues due to its regenerative potential. This potential attributes to a concoction of bioactive molecules secreted by the stem cells, collectively called the secretome, that mediates paracrine and autocrine functions. Among the stem cell types, adipose tissue-derived mesenchymal stem cells (ADMSCs) have been receiving increased attention for its ease of isolation, abundance in tissue and notable impact on improving chronic wound healing. Owing to the reported advantages of cell-free preparations like the secretome over cellular products, developing secretome as a ready-to-use product for wound healing applications seems promising. In this review, we discuss the functional benefits of adipose stem cell secretome in wound healing, the techniques to enrich the secretome and the recommendations for the scale-up and commercialization of secretome products.
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Abbreviations
- ABC-transporter:
-
ATP-binding cassette-transporter
- ADMSCs:
-
Adipose-derived mesenchymal stem cells
- Akt:
-
Protein kinase b
- Ang1:
-
Angiopoietin 1
- bFGF:
-
Basic fibroblast growth factor
- BM:
-
Bone marrow
- BMMSC:
-
Bone marrow mesenchymal stem cells
- cGMP:
-
Current good manufacturing practice
- CM:
-
Conditioned medium
- DC:
-
Dendritic cell
- DF:
-
Dermal fibroblast
- DFU:
-
Diabetic foot ulcer
- DMSO:
-
Dimethyl sulfoxide
- ECM:
-
Extracellular matrix
- ELISA:
-
Enzyme-linked immunosorbent assay
- EC:
-
Endothelial cell
- EGF:
-
Epidermal growth factor
- ER:
-
Endoplasmic reticulum
- ERK/MAPK:
-
Extracellular regulated protein kinases/mitogen-activated protein kinase
- EV:
-
Extracellular vesicle
- FAK:
-
Focal adhesion kinase
- FBS:
-
Fetal bovine serum
- FDA:
-
Food and Drug Administration
- Flk1:
-
Fetal liver kinase 1
- GMP:
-
Good manufacturing practice
- HaCaT:
-
Immortalized human keratinocytes
- HGF:
-
Hepatocyte growth factor
- HIF:
-
Hypoxia-inducible factor
- HPLs:
-
Human platelet lysates
- HUVEC:
-
Human umbilical vein endothelial cells
- ICAT:
-
Isotope-coded affinity tag
- IGF-1:
-
Insulin-like growth factor 1
- IL:
-
Interleukins
- ISEV:
-
International Society of Extracellular Vesicles
- iTRAQ:
-
Isobaric tags for relative and absolute quantitation
- KGF:
-
Keratinocyte growth factor
- LC–MS/MS:
-
Liquid chromatography with tandem mass spectrometry
- lncRNA:
-
Long non-coding RNA
- MALDI-TOF:
-
Matrix-assisted laser desorption/ionization-time of flight
- MAPK:
-
Mitogen-activated protein kinase
- miRNA:
-
MicroRNA
- MISEV:
-
Minimal information for studies of extracellular vesicles
- MMP:
-
Matrix metalloproteinases
- MRM:
-
Multiple reaction monitoring
- MSC:
-
Mesenchymal stem cells
- MV:
-
Microvesicle
- NIH:
-
National Institutes of Health
- NK:
-
Natural killer
- PCNA:
-
Proliferating cell nuclear antigen
- PGDF:
-
Platelet-derived growth factor
- PI3K:
-
Phosphoinositide 3-kinase
- PU:
-
Pressure ulcer
- RePORT:
-
Research Portfolio Online Reporting Tool
- SDS-PAGE:
-
Sodium dodecyl sulfate poly-acrylamide gel electrophoresis
- SFM:
-
Serum free medium
- SILAC:
-
Stable isotope labeling by amino acids in cell culture
- SMAD:
-
Structurally similar proteins
- SVF:
-
Stromal vascular fraction
- TFF:
-
Tangential flow filtration
- TGF:
-
Transforming growth factor
- TIMP:
-
Tissue inhibitor of metalloproteinases
- TNF:
-
Tumor necrosis factor
- VEGF:
-
Vascular endothelial growth factor
- VLU:
-
Venous leg ulcer
- WAT:
-
White adipose tissue
References
Ahangar P, Mills SJ, Cowin AJ (2020) Mesenchymal stem cell secretome as an emerging cell-free alternative for improving wound repair. Int J Mol Sci 21:E7038. https://doi.org/10.3390/ijms21197038
Aiello A, Giannessi F, Percario ZA, Affabris E (2020) An emerging interplay between extracellular vesicles and cytokines. Cytokine Growth Factor Rev 51:49–60. https://doi.org/10.1016/j.cytogfr.2019.12.003
Ajit A, Santhosh TRLK, Krishnan (2019) Engineered human adipose-derived stem cells inducing endothelial lineage and angiogenic response. Tissue Eng Part C Methods 25:148–159. https://doi.org/10.1089/ten.tec.2018.0333
Alt EU, Senst C, Murthy SN et al (2012) Aging alters tissue resident mesenchymal stem cell properties. Stem Cell Res 8:215–225. https://doi.org/10.1016/j.scr.2011.11.002
Bari E, Perteghella S, Di Silvestre D et al (2018a) Pilot production of mesenchymal stem/stromal freeze-dried secretome for cell-free regenerative nanomedicine: a validated GMP-compliant process. Cells 7:190. https://doi.org/10.3390/cells7110190
Bari E, Perteghella S, DiSilvestre D et al (2018b) Pilot production of mesenchymal stem/stromal freeze-dried secretome for cell-free regenerative nanomedicine: a validated GMP-compliant process. Cells 7:190. https://doi.org/10.3390/cells7110190
Barros SD, Dehez S, Arnaud E et al (2013) Aging-related decrease of human ASC angiogenic potential is reversed by hypoxia preconditioning through ROS production. Mol Ther 21:399–408. https://doi.org/10.1038/mt.2012.213
Bennett NT, Schultz GS (1993) Growth factors and wound healing: Part II. Role in normal and chronic wound healing. Am J Surg 166:74–81. https://doi.org/10.1016/S0002-9610(05)80589-6
Berlanga J, Fernández JI, López E et al (2013) Heberprot-P: a novel product for treating advanced diabetic foot ulcer. MEDICC Rev 15:11–15. https://doi.org/10.1590/s1555-79602013000100004
Blume P, Bowlby M, Schmidt BM, Donegan R (2014) Safety and efficacy of Becaplermin gel in the treatment of diabetic foot ulcers. In: Chronic Wound Care Management and Research. https://www.dovepress.com/safety-and-efficacy-of-becaplermin-gel-in-the-treatment-of-diabetic-fo-peer-reviewed-fulltext-article-CWCMR. Accessed 1 Apr 2020
Bogatcheva NV, Coleman ME (2019) Conditioned medium of mesenchymal stromal cells: a new class of therapeutics. Biochem Mosc 84:1375–1389. https://doi.org/10.1134/S0006297919110129
Bourin P, Bunnell BA, Casteilla L et al (2013) Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy 15:641–648. https://doi.org/10.1016/j.jcyt.2013.02.006
Casado-Díaz A, Quesada-Gómez JM, Dorado G (2020) Extracellular vesicles derived from mesenchymal stem cells (MSC) in regenerative medicine: applications in skin wound healing. Front Bioeng Biotechnol 8:146. https://doi.org/10.3389/fbioe.2020.00146
Cerqueira MT, Pirraco RP, Marques AP (2016) Stem cells in skin wound healing: are we there yet? Adv Wound Care 5:164–175. https://doi.org/10.1089/wound.2014.0607
Chu D-T, Nguyen Thi Phuong T, Tien NLB et al (2019) Adipose tissue stem cells for therapy: an update on the progress of isolation, culture, storage, and clinical application. J Clin Med 8:917. https://doi.org/10.3390/jcm8070917
Coalson E, Bishop E, Liu W et al (2019) Stem cell therapy for chronic skin wounds in the era of personalized medicine: From bench to bedside. Genes Dis 6:342–358. https://doi.org/10.1016/j.gendis.2019.09.008
Cowper M, Frazier T, Wu X et al (2019) Human platelet lysate as a functional substitute for fetal bovine serum in the culture of human adipose derived stromal/stem cells. Cells 8:724. https://doi.org/10.3390/cells8070724
Dekoninck S, Blanpain C (2019) Stem cell dynamics, migration and plasticity during wound healing. Nat Cell Biol 21:18–24. https://doi.org/10.1038/s41556-018-0237-6
Deng C, He Y, Feng J et al (2019) Conditioned medium from 3D culture system of stromal vascular fraction cells accelerates wound healing in diabetic rats. Regen Med 14:925–937. https://doi.org/10.2217/rme-2018-0083
Driscoll J, Patel T (2019) The mesenchymal stem cell secretome as an acellular regenerative therapy for liver disease. J Gastroenterol 54:763–773. https://doi.org/10.1007/s00535-019-01599-1
Duscher D, Barrera J, Wong VW et al (2016) Stem cells in wound healing: the future of regenerative medicine? A mini-review. Gerontology 62:216–225. https://doi.org/10.1159/000381877
Ebrahimian TG, Pouzoulet F, Squiban C et al (2009) Cell therapy based on adipose tissue-derived stromal cells promotes physiological and pathological wound healing. Arterioscler Thromb Vasc Biol 29:503–510. https://doi.org/10.1161/ATVBAHA.108.178962
Ellison-Hughes GM, Madeddu P (2017) Exploring pericyte and cardiac stem cell secretome unveils new tactics for drug discovery. Pharmacol Ther 171:1–12. https://doi.org/10.1016/j.pharmthera.2016.11.007
Eming SA, Martin P, Tomic-Canic M (2014) Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med 6:265sr6-265sr6. https://doi.org/10.1126/scitranslmed.3009337
Fernández-Montequín JI, Betancourt BY, Leyva-Gonzalez G et al (2009) Intralesional administration of epidermal growth factor-based formulation (Heberprot-P) in chronic diabetic foot ulcer: treatment up to complete wound closure. Int Wound J 6:67–72. https://doi.org/10.1111/j.1742-481X.2008.00561.x
Ferreira JR, Teixeira GQ, Santos SG et al (2018) Mesenchymal stromal cell secretome: influencing therapeutic potential by cellular pre-conditioning. Front Immunol 9:2837. https://doi.org/10.3389/fimmu.2018.02837
Fitzgerald W, Freeman ML, Lederman MM et al (2018) A system of cytokines encapsulated in extracellular vesicles. Sci Rep 8:8973. https://doi.org/10.1038/s41598-018-27190-x
Frykberg RG, Banks J (2015) Challenges in the treatment of chronic wounds. Adv Wound Care 4:560–582. https://doi.org/10.1089/wound.2015.0635
Traversa B, Sussman G (2001) The role of growth factors, cytokines and proteases in wound management. Primary Intention: Australian J Wound Manage 9(4):161–167
Gangaraju RS, Sohl NMJ, Jotterand VH, Pentecost M (2019) Adipose tissue derived mesenchymal stromal cell conditioned media and methods of making and using the same. U.S. Patent Application No. 16/076,511
Gimona M, Pachler K, Laner-Plamberger S et al (2017) Manufacturing of human extracellular vesicle-based therapeutics for clinical use. Int J Mol Sci 18:1190. https://doi.org/10.3390/ijms18061190
Gnecchi M, He H, Liang OD et al (2005) Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med 11:367–368. https://doi.org/10.1038/nm0405-367
Gnecchi M, He H, Noiseux N et al (2006) Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J 20:661–669. https://doi.org/10.1096/fj.05-5211com
Gonzalez de ACO, Costa TF, Andrade de ZA, Medrado ARAP (2016) Wound healing—a literature review. An Bras Dermatol 91:614–620. https://doi.org/10.1590/abd1806-4841.20164741
Gowen A, Shahjin F, Chand S et al (2020) Mesenchymal stem cell-derived extracellular vesicles: challenges in clinical applications. Front Cell Dev Biol 8:149. https://doi.org/10.3389/fcell.2020.00149
Harrell CR, Fellabaum C, Jovicic N et al (2019) Molecular mechanisms responsible for therapeutic potential of mesenchymal stem cell-derived secretome. Cells 8:467. https://doi.org/10.3390/cells8050467
Hassan WU, Greiser U, Wang W (2014) Role of adipose-derived stem cells in wound healing: role of ASCs in wound healing. Wound Repair Regen 22:313–325. https://doi.org/10.1111/wrr.12173
Hourd P, Chandra A, Medcalf N, Williams DJ (2008) Regulatory challenges for the manufacture and scale-out of autologous cell therapies. In: StemBook. Harvard Stem Cell Institute, Cambridge, MA
Hu C, Li L (2018) Preconditioning influences mesenchymal stem cell properties in vitro and in vivo. J Cell Mol Med 22:1428–1442. https://doi.org/10.1111/jcmm.13492
Hu L, Wang J, Zhou X et al (2016) Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts. Sci Rep 6:32993. https://doi.org/10.1038/srep32993
Julianto I, Rindastuti Y (2016) Topical delivery of mesenchymal stem cells “Secretomes” in wound repair. Acta Medica Indones 48:217–220
Kaddoura I, Abu-Sittah G, Ibrahim A et al (2017) Burn injury: review of pathophysiology and therapeutic modalities in major burns. Ann Burns Fire Disasters 30:95–102
Kakudo N, Morimoto N, Ma Y, Kusumoto K (2019) Differences between the proliferative effects of human platelet lysate and fetal bovine serum on human adipose-derived stem cells. Cells 8:1218. https://doi.org/10.3390/cells8101218
Kalinina N, Kharlampieva D, Loguinova M et al (2015) Characterization of secretomes provides evidence for adipose-derived mesenchymal stromal cells subtypes. Stem Cell Res Ther 6:221. https://doi.org/10.1186/s13287-015-0209-8
Kanji S, Das H (2017) Advances of stem cell therapeutics in cutaneous wound healing and regeneration. Mediators Inflamm 2017:1–14. https://doi.org/10.1155/2017/5217967
Kim W-S, Park B-S, Sung J-H et al (2007) Wound healing effect of adipose-derived stem cells: a critical role of secretory factors on human dermal fibroblasts. J Dermatol Sci 48:15–24. https://doi.org/10.1016/j.jdermsci.2007.05.018
Kim MH, Wu WH, Choi JH et al (2018) Galectin-1 from conditioned medium of three-dimensional culture of adipose-derived stem cells accelerates migration and proliferation of human keratinocytes and fibroblasts: effects of galectin-1 from 3D-cultured ADSC in wound healing. Wound Repair Regen 26:S9–S18. https://doi.org/10.1111/wrr.12579
Kraskiewicz H, Paprocka M, Bielawska-Pohl A et al (2020) Can supernatant from immortalized adipose tissue MSC replace cell therapy? An in vitro study in chronic wounds model. Stem Cell Res Ther 11:29. https://doi.org/10.1186/s13287-020-1558-5
Krzyszczyk P, Schloss R, Palmer A, Berthiaume F (2018) The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes. Front Physiol 9:419. https://doi.org/10.3389/fphys.2018.00419
Kupcova Skalnikova H (2013) Proteomic techniques for characterisation of mesenchymal stem cell secretome. Biochimie 95:2196–2211. https://doi.org/10.1016/j.biochi.2013.07.015
Laggner M, Gugerell A, Bachmann C et al (2020) Reproducibility of GMP-compliant production of therapeutic stressed peripheral blood mononuclear cell-derived secretomes, a novel class of biological medicinal products. Stem Cell Res Ther 11:9. https://doi.org/10.1186/s13287-019-1524-2
Lee SH, Jin SY, Song JS et al (2012) Paracrine effects of adipose-derived stem cells on keratinocytes and dermal fibroblasts. Ann Dermatol 24:136–143. https://doi.org/10.5021/ad.2012.24.2.136
Li P, Guo X (2018) A review: therapeutic potential of adipose-derived stem cells in cutaneous wound healing and regeneration. Stem Cell Res Ther 9:302. https://doi.org/10.1186/s13287-018-1044-5
Liang X, Zhang L, Wang S et al (2016) Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a. J Cell Sci 129:2182–2189. https://doi.org/10.1242/jcs.170373
Lombardi F, Palumbo P, Augello FR et al (2019a) Secretome of adipose tissue-derived stem cells (ASCs) as a novel trend in chronic non-healing wounds: an overview of experimental in vitro and in vivo studies and methodological variables. Int J Mol Sci 20:3721. https://doi.org/10.3390/ijms20153721
Lombardi F, Palumbo P, Augello FR et al (2019b) Secretome of adipose tissue-derived stem cells (ASCs) as a novel trend in chronic non-healing wounds: an overview of experimental in vitro and in vivo studies and methodological variables. Int J Mol Sci 20:3721. https://doi.org/10.3390/ijms20153721
Lötvall J, Hill AF, Hochberg F et al (2014) Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles 3:913. https://doi.org/10.3402/jev.v3.26913
Maacha S, Sidahmed H, Jacob S et al (2020) Paracrine mechanisms of mesenchymal stromal cells in angiogenesis. Stem Cells Int 2020:4356359. https://doi.org/10.1155/2020/4356359
Maguire G (2019) The safe and efficacious use of secretome from fibroblasts and adipose-derived (but not bone marrow-derived) mesenchymal stem cells for skin therapeutics. J Clin Aesthetic Dermatol 12:E57–E69
Manferdini C, Paolella F, Gabusi E et al (2017) Adipose stromal cells mediated switching of the pro-inflammatory profile of M1-like macrophages is facilitated by PGE2: in vitro evaluation. Osteoarthritis Cartilage 25:1161–1171. https://doi.org/10.1016/j.joca.2017.01.011
Mardpour S, Hamidieh AA, Taleahmad S et al (2019) Interaction between mesenchymal stromal cell-derived extracellular vesicles and immune cells by distinct protein content. J Cell Physiol 234:8249–8258. https://doi.org/10.1002/jcp.27669
Martin P, Nunan R (2015) Cellular and molecular mechanisms of repair in acute and chronic wound healing. Br J Dermatol 173:370–378. https://doi.org/10.1111/bjd.13954
Mastrolia I, Foppiani EM, Murgia A et al (2019) Challenges in clinical development of mesenchymal stromal/stem cells: concise review. Stem Cells Transl Med 8:1135–1148. https://doi.org/10.1002/sctm.19-0044
McKernan R, McNeish J, Smith D (2010) Pharma’s developing interest in stem cells. Cell Stem Cell 6:517–520. https://doi.org/10.1016/j.stem.2010.05.012
Mizukami A, Swiech K (2018) Mesenchymal stromal cells: from discovery to manufacturing and commercialization. Stem Cells Int 2018:4083921. https://doi.org/10.1155/2018/4083921
Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11:723–737. https://doi.org/10.1038/nri3073
Niada S, Giannasi C, Gualerzi A et al (2018) Differential proteomic analysis predicts appropriate applications for the secretome of adipose-derived mesenchymal stem/stromal cells and dermal fibroblasts. Stem Cells Int 2018:1–11. https://doi.org/10.1155/2018/7309031
Nickel W, Rabouille C (2009) Mechanisms of regulated unconventional protein secretion. Nat Rev Mol Cell Biol 10:148–155. https://doi.org/10.1038/nrm2617
Noronha de NC, Mizukami A, Caliári-Oliveira C et al (2019) Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies. Stem Cell Res Ther 10:131. https://doi.org/10.1186/s13287-019-1224-y
Olsson M, Järbrink K, Divakar U et al (2019) The humanistic and economic burden of chronic wounds: a systematic review: the burden of chronic wounds. Wound Repair Regen 27:114–125. https://doi.org/10.1111/wrr.12683
Pang C, Ibrahim A, Bulstrode NW, Ferretti P (2017) An overview of the therapeutic potential of regenerative medicine in cutaneous wound healing: advances and limitations in regenerative medicine for stimulating wound repair. Int Wound J 14:450–459. https://doi.org/10.1111/iwj.12735
Park S-R, Kim J-W, Jun H-S et al (2018) Stem cell secretome and its effect on cellular mechanisms relevant to wound healing. Mol Ther 26:606–617. https://doi.org/10.1016/j.ymthe.2017.09.023
Pastar I, Wong LL, Egger AN, Tomic-Canic M (2018) Descriptive vs mechanistic scientific approach to study wound healing and its inhibition: is there a value of translational research involving human subjects? Exp Dermatol 27:551–562. https://doi.org/10.1111/exd.13663
Peng W, Gao T, Yang Z et al (2012) Adipose-derived stem cells induced dendritic cells undergo tolerance and inhibit Th1 polarization. Cell Immunol 278:152–157. https://doi.org/10.1016/j.cellimm.2012.07.008
Pinho AG, Cibrão JR, Silva NA et al (2020) Cell secretome: basic insights and therapeutic opportunities for CNS disorders. Pharmaceuticals 13:31. https://doi.org/10.3390/ph13020031
Raghava PGS (2020) THPdb: a database of FDA approved therapeutic peptides and proteins
Raposio E, Simonacci F, Perrotta RE (2017) Adipose-derived stem cells: comparison between two methods of isolation for clinical applications. Ann Med Surg 20:87–91. https://doi.org/10.1016/j.amsu.2017.07.018
Ren S, Chen J, Duscher D et al (2019) Microvesicles from human adipose stem cells promote wound healing by optimizing cellular functions via AKT and ERK signaling pathways. Stem Cell Res Ther 10:47. https://doi.org/10.1186/s13287-019-1152-x
Revilla A, González C, Iriondo A et al (2016) Current advances in the generation of human iPS cells: implications in cell-based regenerative medicine. J Tissue Eng Regen Med 10:893–907. https://doi.org/10.1002/term.2021
Ribeiro A, Laranjeira P, Mendes S et al (2013) Mesenchymal stem cells from umbilical cord matrix, adipose tissue and bone marrow exhibit different capability to suppress peripheral blood B, natural killer and T cells. Stem Cell Res Ther 4:125. https://doi.org/10.1186/scrt336
Riis S, Stensballe A, Emmersen J et al (2016) Mass spectrometry analysis of adipose-derived stem cells reveals a significant effect of hypoxia on pathways regulating extracellular matrix. Stem Cell Res Ther 7:52. https://doi.org/10.1186/s13287-016-0310-7
Robert AW, Azevedo Gomes F, Rode MP et al (2019) The skin regeneration potential of a pro-angiogenic secretome from human skin-derived multipotent stromal cells. J Tissue Eng 10:2041731419833391. https://doi.org/10.1177/2041731419833391
Rodrigues M, Kosaric N, Bonham CA, Gurtner GC (2019) Wound healing: a cellular perspective. Physiol Rev 99:665–706. https://doi.org/10.1152/physrev.00067.2017
Rohde E, Pachler K, Gimona M (2019) Manufacturing and characterization of extracellular vesicles from umbilical cord-derived mesenchymal stromal cells for clinical testing. Cytotherapy 21:581–592. https://doi.org/10.1016/j.jcyt.2018.12.006
Schipper BM, Marra KG, Zhang W et al (2008) Regional anatomic and age effects on cell function of human adipose-derived stem cells. Ann Plast Surg 60:538–544. https://doi.org/10.1097/SAP.0b013e3181723bbe
Schira-Heinen J, Grube L, Waldera-Lupa DM et al (2019) Pitfalls and opportunities in the characterization of unconventionally secreted proteins by secretome analysis. Biochim Biophys Acta BBA Proteins Proteomics 1867:140237. https://doi.org/10.1016/j.bbapap.2019.06.004
Schnitzler AC, Verma A, Kehoe DE et al (2016) Bioprocessing of human mesenchymal stem/stromal cells for therapeutic use: current technologies and challenges. Biochem Eng J 108:3–13. https://doi.org/10.1016/j.bej.2015.08.014
Schultz GS, Mast BA (1999) Molecular analysis of the environments of healing and chronic wounds: cytokines, proteases and growth factors. Primary Intention 7:7–15
Sen CK (2019) Human wounds and its burden: an updated compendium of estimates. Adv Wound Care 8:39–48. https://doi.org/10.1089/wound.2019.0946
Song P, Kwon Y, Joo J-Y et al (2019) Secretomics to discover regulators in diseases. Int J Mol Sci 20:3893. https://doi.org/10.3390/ijms20163893
Sun DZ, Abelson B, Babbar P, Damaser MS (2019) Harnessing the mesenchymal stem cell secretome for regenerative urology. Nat Rev Urol 16:363–375. https://doi.org/10.1038/s41585-019-0169-3
ten Ham RMT, Nievaart JC, Hoekman J et al (2021) Estimation of manufacturing development costs of cell-based therapies: a feasibility study. Cytotherapy. https://doi.org/10.1016/j.jcyt.2020.12.014
Théry C, Witwer KW, Aikawa E et al (2018) Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 7:1535750. https://doi.org/10.1080/20013078.2018.1535750
Tran C, Damaser MS (2015) Stem cells as drug delivery methods: application of stem cell secretome for regeneration. Adv Drug Deliv Rev 82–83:1–11. https://doi.org/10.1016/j.addr.2014.10.007
Trounson A, Baum E, Gibbons D, Tekamp-Olson P (2010) Developing a case study model for successful translation of stem cell therapies. Cell Stem Cell 6:513–516. https://doi.org/10.1016/j.stem.2010.05.008
Velnar T, Bailey T, Smrkolj V (2009) The wound healing process: an overview of the cellular and molecular mechanisms. J Int Med Res 37:1528–1542. https://doi.org/10.1177/147323000903700531
Vizoso F, Eiro N, Cid S et al (2017) Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine. Int J Mol Sci 18:1852. https://doi.org/10.3390/ijms18091852
Vulto AG, Jaquez OA (2017) The process defines the product: what really matters in biosimilar design and production? Rheumatol Oxf Engl 56:iv14–iv29. https://doi.org/10.1093/rheumatology/kex278
Wang L, Hu L, Zhou X et al (2017) Exosomes secreted by human adipose mesenchymal stem cells promote scarless cutaneous repair by regulating extracellular matrix remodelling. Sci Rep 7:13321. https://doi.org/10.1038/s41598-017-12919-x
Wang M, Yuan Q, Xie L (2018) Mesenchymal stem cell-based immunomodulation: properties and clinical application. Stem Cells Int 2018:3057624. https://doi.org/10.1155/2018/3057624
Waters R, Subham S, Pacelli S et al (2019) Development of MicroRNA-146a-enriched stem cell secretome for wound-healing applications. Mol Pharm 16:4302–4312. https://doi.org/10.1021/acs.molpharmaceut.9b00639
Wu P, Zhang B, Shi H et al (2018) MSC-exosome: a novel cell-free therapy for cutaneous regeneration. Cytotherapy 20:291–301. https://doi.org/10.1016/j.jcyt.2017.11.002
Yamakawa S, Hayashida K (2019) Advances in surgical applications of growth factors for wound healing. Burns Trauma 7:10. https://doi.org/10.1186/s41038-019-0148-1
Zhang Y, Liu Y, Liu H, Tang WH (2019) Exosomes: biogenesis, biologic function and clinical potential. Cell Biosci 9:19. https://doi.org/10.1186/s13578-019-0282-2
Acknowledgements
The authors acknowledge the financial support provided by the research project grants awarded to Dr. Amita Ajit under the Women Scientist Scheme-A (WoS-A), Department of Science and Technology, New Delhi, Government of India and the Kerala State Council for Science, Technology & Environment (KSCSTE), Ministry of Science and Technology, Government of Kerala (GOK), which formed the basis of this work.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. However, the basis of this work was financially supported by the research project grants under the Women Scientist Scheme-A (WoS-A), Department of Science and Technology, New Delhi, Government of India and the Kerala State Council for Science, Technology & Environment (KSCSTE), Ministry of Science and Technology, Government of Kerala (GOK).
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Dr. AA and AGI conceptualized the study, collected the resources, validated, drafted, and reviewed the manuscript. Dr. AA developed the idea and AGI did the illustrations.
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Ajit, A., Ambika Gopalankutty, I. Adipose-derived stem cell secretome as a cell-free product for cutaneous wound healing. 3 Biotech 11, 413 (2021). https://doi.org/10.1007/s13205-021-02958-7
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DOI: https://doi.org/10.1007/s13205-021-02958-7