Extracellular Vesicles as Therapeutic Tools for the Treatment of Chronic Wounds
Abstract
:1. Introduction
2. From Mesenchymal Stem Cells to Extracellular Vesicles
2.1. Lessons Learned from Mesenchymal Stem Cells
2.2. Extracellular Vesicles
3. Role for MSC Extracellular Vesicles in Wound Healing
Study | EV Source | Model | Findings |
---|---|---|---|
Fang et al. 2016 [77] | Human UC-MSC | Mouse skin wound -Local injection | EVs reduced scar formation and myofibroblast accumulation. |
In vitro dermal fibroblasts | EVs suppressed TGF-β induced myofibroblast formation. EVs were enriched in miR-21, miR-23a, miR-125b, and miR-145. miRNA delivery reduced TGF-β/SMAD2 signaling in fibroblasts. | ||
Hu et al. 2016 [78] | Human AD-MSC | Mouse skin wound -Local injection | EVs improved rate of wound healing, increased Col1 and Col3 mRNA on Day 3 and Day 5 post wounding, and decreased Col1 and Col3 mRNA on Days 7 and 14. |
Mouse skin wound -Intravenous injection | EVs migrated to wound site (Days 5–14) and spleen and promoted wound healing. | ||
In vitro fibroblasts | EVs promoted fibroblast proliferation and migration, increased mRNA for N-cadherin, COL1, COL3, and elastin. | ||
Zhang et al. 2018 [79] | Human AD-MSC | Mouse skin wound -Local injection | EVs improved rate of wound healing, decreased scar size, and neoangiogenesis. |
In vitro fibroblasts | EVs promoted fibroblast proliferation and migration, and increased mRNA for COL1, COL3, MMP1, FGF2, and TGF-β1. Fibroblasts had increased p-AKT. Application of PI3K/AKT inhibitor Ly294002 abrogated the EV-induced effects on fibroblasts. | ||
He et al. 2019 [80] | Human BM-MSC | Mouse skin wound -Intravenous injection | EVs promoted wound healing and polarization of macrophages to M2 phenotype. |
In vitro human monocytes/macrophages | EVs promoted M2 macrophage polarization in part through transfer of miR-223. | ||
Ren et al. 2019 [81] | Human AD-MSC | Mouse skin wound -Local injection | EVs accelerated wound healing, re-epithelialization, collagen deposition, and neovascularization. |
In vitro fibroblasts, keratinocytes (HaCaT), and endothelial cells (HUVEC) | EVs promoted proliferation and migration, and stimulated AKT and ERK signaling. | ||
Cheng et al. 2020 [82] | Human UC-MSC | Mouse skin wound -Local injection | EVs accelerated re-epithelialization and promoted collagen fiber maturation. |
In vitro dermal fibroblasts and keratinocytes (HaCaT) | EVs promoted proliferation and migration. The effect was blocked by miR-27b inhibitor. Proposed miR-27b acts by suppressing ITCH, thereby activating JUNB/IRE1α. | ||
Jiang et al. 2020 [83] | Human BM-MSC | Mouse skin wound -Local injection | EVs from MSCs with TSG-6 overexpression (TSG-6-EVs) and knock-down (TSG-6-KD-EVs). EVs reduced scar formation, reduced production of TGF-β1, Collagen I and III, and αSMA protein, and suppressed SMAD2/3 signaling. TSG-6-EVs enhanced the effect of EVs, the effect was lost in TSG-6-KD-EVs, and when TSG-6 neutralizing antibodies were present. |
Liu et al. 2020 [84] | Mouse BM-MSC | Mouse skin wound -Topical in Pluronic F127 hydrogel | Topical EVs accelerated wound healing, limited inflammatory infiltrate, and decreased scar size. |
In vitro mouse macrophages | EVs polarized macrophages towards M2 phenotype. Conditioned media from EV treated macrophages promoted fibroblast proliferation and migration. | ||
Qiu et al. 2020 [85] | Mouse BM-MSC | Mouse skin wound -Local injection | EVs from MSCs treated with EVs from neonatal serum and adult serum. MSC-EVs accelerated wound healing and promoted neoangiogenesis. Neonatal serum stimulated MSC-EVs showed more robust effect. |
In vitro endothelial cells (HUVECs) | MSC-EVs promoted HUVEC proliferation, migration, and tube formation, and increased p-AKT and p-eNOS. Neonatal serum stimulated MSC-EVs showed more robust effect. | ||
Zhang et al. 2020 [86] | Human AD-MSC | Mouse skin wound -Local injection | EVs promoted mouse wound healing, proposed to occur in AKT/HIF-1α dependent fashion. |
In vitro HaCaT Keratinocytes | EVs promoted HaCaT keratinocyte proliferation. | ||
Zhao et al. 2020 [87] | Human UC-MSC | Mouse skin wound -Local injection | EVs enhanced re-epithelialization and neoangiogenesis. |
In vitro keratinocytes (HaCaT) | EVs stimulated keratinocyte proliferation, migration, and suppressed ROS induced apoptosis. Proposed effect was through suppression of AIF nuclear translocation and PARP-1 activation. | ||
Li et al. 2021 [88] | Human AD-MSC | In vitro human hypertrophic scar fibroblasts | EVs decreased collagen deposition, trans-differentiation of fibroblasts-to-myofibroblasts, and formation of hypertrophic scar. EVs were noted to express miR-192-5p, which can suppress IL-17RA/SMAD axis. |
Diabetic wounds: | |||
Wang et al. 2019 [89] | Mouse AD-MSC | Mouse diabetic wound -Topical in complex hydrogel (Pluronic F127, oxidative hyaluronic acid, and Poly-l-lysine) | EVs improved wound healing and neovascularization. The effect was improved when EVs were loaded in complex hydrogel. |
Li et al. 2020 [90] | Mouse BM-MSC | Mouse diabetic wound -Local injection | EVs from MSCs overexpressing lncRNA H19 (H19-EVs). Only H19-EVs promoted wound healing, decreased inflammatory infiltrate, and increased granulation tissue formation. |
In vitro human fibroblasts from diabetic foot ulcers and health control | H19-EVs reduced miR-152-3p expression in fibroblasts from diabetics and increased PTEN expression. | ||
Shi et al. 2020 [91] | Mouse AD-MSC | Mouse diabetic wound -Local injection | EVs accelerated wound healing, increased angiogenesis, suppressed apoptosis, and increased autophagy markers SIRT1 and LC3. The effects were further enhanced with EVs from mmu_circ_0000250 overexpressing MSCs. |
In vitro endothelial cells (HUVECs) | EVs promoted HUVEC survival under high glucose conditions and increased autophagy. This was enhanced by loading with mmu_circ_0000250, which was shown to increase SIRT1 mediated autophagy. | ||
Yang et al. 2020 [92] | Human UC-MSC | Mouse diabetic wound -Topical in Pluronic F127 hydrogel | EVs accelerated wound healing and angiogenesis, increased expression of VEGF and TGF-β1. |
Pomatto et al. 2021 [93] | Human BM-MSC AD-MSC | Mouse diabetic wound -Topical in carboxymethylcellulose | AD-MSC-EVs, but not BM-MSC-EVs, promoted the rate of wound healing. Comparative in vivo analysis of scar and angiogenesis was not performed. |
In vitro fibroblasts, keratinocytes, and endothelial cells | BM-MSC-EVs promoted proliferation of keratinocytes and endothelial cells, and promoted viability of fibroblasts, keratinocytes, and endothelial cells. AD-MSC-EVs promoted only the proliferation of endothelial cells. Protein and miRNA analysis indicated BM-MSC-EVs are enriched for proliferative factors, whereas AD-MSC-EVs are enriched in proangiogenic factors. | ||
Ti et al. 2015 [94] | Human UC-MSC | Rat diabetic wound -Local injection | EVs from LPS preconditioned MSCs (LPS Pre-EVs) decreased inflammatory cell infiltration and polarized macrophages towards M2. |
In vitro human monocytes (THP-1) | LPS Pre-EVs induced M2 polarization. EVs transferred Let-7b, reducing TLR-4 expression and NF-kB activation. | ||
Li et al. 2018 [95] | Human AD-MSC | Rat diabetic wound | EVs from MSCs overexpressing NRF2 (NRF2-EVs).Endothelial progenitor cells (EPC) + NRF2-EVs promoted wound healing better than EPC + AD-MSC-EVs, and both were better than EPC alone or control. |
In vitro human epithelial progenitor cells (EPC) | EVs decreased EPC senescence under high glucose conditions. NRF2-EVs inhibited inflammatory cytokines and ROS. | ||
Ding et al. 2019 [96] | Human BM-MSC | Rat diabetic wound -Local injection | EVs from deferoxamine stimulated MSCs (DFO-EVs). EVs promoted wound healing and neoangiogenesis, and DFO-EVs were more effective. |
In vitro endothelial cells (HUVECs) | DFO-EVs were more potent stimulators of HUVEC proliferation and tube formation than EVs. DFO-EVs proposed to transfer miR-126 to HUVECs, which suppresses PTEN, and thereby activates AKT signaling. | ||
Liu et al. 2020 [97] | Human BM-MSC | Rat diabetic wound -Local injection | EVs from MSCs treated with melatonin (MT-EVs). EVs promoted wound closure, Collagen I and III expression, and M2 macrophage polarization; MT-EVs enhanced the effect of EVs. |
In vitro mouse macrophages (RAW264.7) | MT-EVs were more potent than EVs at polarizing macrophages to M2 phenotype. | ||
Yu et al. 2020 [98] | Human BM-MSC | Rat diabetic wound -Local injection | EVs from MSCs treated with atorvastatin (ATV-EVs). EVs promoted wound healing and angiogenesis. ATV-EVs were more effective. |
In vitro endothelial cells (HUVECs) | EVs promoted proliferation, migration, and tube formation, increased VEGF secretion, and activated AKT/eNOS signaling. ATV-EVs produce a larger magnitude effect compared to standard EVs. ATV-EVs proposed to work by upregulating miR-221-3p in endothelial cells. | ||
Burn wounds: | |||
Shafei et al. 2020 [99] | Human AD-MSC | Mouse burn wound -Topical in alginate hydrogel | EVs accelerated wound closure, increased epithelial thickness, collagen deposition, and neovascularization. |
Zhang et al. 2015 [100] | Human iPSC-MSC | Rat burn wound -Local injection | EVs accelerated re-epithelialization, reduced scar width, promoted collagen maturation, and stimulated neoangiogenesis. Effects depended on EV transfer of Wnt4. |
In vitro fibroblasts and endothelial cells (HUVECs) | EVs stimulated proliferation and migration, stimulated Collagen I and III, and elastin secretion, and promoted tube formation. | ||
Li et al. 2016 [101] | Human UC-MSC | Rat burn wound -Intravenous injection | EVs reduce inflammation following burn wounds. EVs transfer miR-181c and reduce TLR4 signaling. |
In vitro mouse macrophages (RAW264.7) | EVs suppress LPS induced macrophage inflammation. |
3.1. Inflammation
3.2. Proliferation
3.3. Remodeling
4. Tailoring EVs to Heal Chronic Wounds
4.1. Extracellular Vesicles: Source
4.2. Extracellular Vesicles: Engineering
4.3. Extracellular Vesicles: Quality Control
4.4. Extracellular Vesicles: Delivery
5. Clinical Perspectives
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AIF | Apoptosis-inducing factor |
CCR7 | C-C motif chemokine receptor 7 |
COL7A1 | Collagen VII alpha 1 chain |
CM | Conditioned media |
DC | Dendritic cell |
ECM | Extracellular matrix |
EGF | Epithelial growth factor |
eNOS | Endothelial NOS |
ESCRT | Endosomal sorting complex required for transport |
EV | Extracellular vesicle |
FHE | Pluronic F127, hyaluronic acid, and poly-[epsilon]-L-lysine |
FGF | Fibroblast growth factor |
FOXP3 | Forkhead box P3 |
HIF-1α | Hypoxia inducible factor-1-alpha |
IL | Interleukin |
IL-1RA | Interleukin 1 receptor antagonist |
IL-17RA | Interleukin 17 receptor A |
IFN | Interferon |
IGF-1 | Insulin-like growth factor 1 |
IRE1α | Inositol requiring enzyme-1-alpha |
IV | Intravenous |
kDa | kilodalton |
LPS | Lipopolysaccharide |
MMP-9 | Matrix metalloproteinase 9 |
NRF2 | Nuclear factor erythroid 2 like 2 |
OCT4 | Octamer-binding protein 4 |
PARP1 | Poly (ADP-ribose) polymerase-1 |
PDGF | Platelet-derived growth factor |
PTEN | Phosphate and Tensin homolog |
ROS | Reactive oxygen species |
STAT3 | Signal transducer and activator of transcription 3 |
SIRPα | Signal regulatory protein alpha |
TGF-β | Tissue growth factor beta |
THBS1 | Thrombospondin 1 |
TLR | Toll-like receptor |
TNF-α | Tumor necrosis factor alpha |
Tregs | Regulatory T lymphocyte |
TSG-6 | Tumor necrosis factor-stimulated gene-6 |
VEGF | Vascular endothelial growth factor |
MSC | Mesenchymal stem cell |
BM-MSC | Bone marrow MSC |
AD-MSC | Adipose tissue MSC |
UC-MSC | Umbilical cord MSC |
mRNA | Messenger RNA |
mtDNA | Mitochondrial DNA |
rRNA | Ribosomal RNA |
tRNA | Transfer RNA |
lncRNA | Long noncoding RNA |
circRNA | Circular RNA |
piRNA | picoRNA |
References
- Li, J.; Chen, J.; Kirsner, R. Pathophysiology of acute wound healing. Clin. Dermatol. 2007, 25, 9–18. [Google Scholar] [CrossRef]
- Gurtner, G.C.; Werner, S.; Barrandon, Y.; Longaker, M.T. Wound repair and regeneration. Nature 2008, 453, 314–321. [Google Scholar] [CrossRef]
- Lazarus, G.S.; Cooper, D.M.; Knighton, D.R.; Margolis, D.J.; Percoraro, R.E.; Rodeheaver, G.; Robson, M.C. Definitions and guidelines for assessment of wounds and evaluation of healing. Wound Repair Regen. 1994, 2, 165–170. [Google Scholar] [CrossRef]
- Bickers, D.R.; Lim, H.W.; Margolis, D.; Weinstock, M.A.; Goodman, C.; Faulkner, E.; Gould, C.; Gemmen, E.; Dall, T. The burden of skin diseases: 2004: A joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J. Am. Acad. Dermatol. 2006, 55, 490–500. [Google Scholar] [CrossRef] [PubMed]
- Franks, P.J.; Moffatt, C.J.; Doherty, D.C.; Smithdale, R.; Martin, R. Longer-term changes in quality of life in chronic leg ulceration. Wound Repair Regen. 2006, 14, 536–541. [Google Scholar] [CrossRef] [PubMed]
- Hopman, W.M.; Harrison, M.B.; Coo, H.; Friedberg, E.; Buchanan, M.; VanDenKerkhof, E.G. Associations between chronic disease, age and physical and mental health status. Chronic Dis. Can. 2009, 29, 108–116. [Google Scholar] [CrossRef]
- Singer, A.J.; Tassiopoulos, A.; Kirsner, R.S. Evaluation and Management of Lower-Extremity Ulcers. N. Engl. J. Med. 2017, 377, 1559–1567. [Google Scholar] [CrossRef] [PubMed]
- Han, C.-M.; Cheng, B.; Wu, P.; Writing Group of Growth Factor Guideline on Behalf of Chinese Burn Association. Clinical guideline on topical growth factors for skin wounds. Burn. Trauma 2020, 8, tkaa035. [Google Scholar] [CrossRef] [PubMed]
- Oropallo, A.R. Use of Native Type I Collagen Matrix Plus Polyhexamethylene Biguanide for Chronic Wound Treatment. Plast. Reconstr. Surg. Glob. Open 2019, 7, e2047. [Google Scholar] [CrossRef] [PubMed]
- Dai, C.; Shih, S.; Khachemoune, A. Skin substitutes for acute and chronic wound healing: An updated review. J. Dermatol. Treat. 2020, 31, 639–648. [Google Scholar] [CrossRef]
- Frykberg, R.G.; Banks, J. Challenges in the Treatment of Chronic Wounds. Adv. Wound Care 2015, 4, 560–582. [Google Scholar] [CrossRef] [Green Version]
- Butler, K.L.; Goverman, J.; Ma, H.; Fischman, A.; Yu, Y.-M.; Bilodeau, M.; Rad, A.M.; Bonab, A.A.; Tompkins, R.G.; Fagan, S.P. Stem Cells and Burns: Review and Therapeutic Implications. J. Burn. Care Res. 2010, 31, 874–881. [Google Scholar] [CrossRef]
- Kucharzewski, M.; Rojczyk, E.; Wilemska-Kucharzewska, K.; Wilk, R.; Hudecki, J.; Los, M.J. Novel trends in application of stem cells in skin wound healing. Eur. J. Pharmacol. 2018, 843, 307–315. [Google Scholar] [CrossRef]
- Duscher, D.; Barrera, J.F.; Wong, V.W.; Maan, Z.; Whittam, A.J.; Januszyk, M.; Gurtner, G.C. Stem Cells in Wound Healing: The Future of Regenerative Medicine? A Mini-Review. Gerontology 2015, 62, 216–225. [Google Scholar] [CrossRef]
- Bianco, P. “Mesenchymal” Stem Cells. Annu. Rev. Cell Dev. Biol. 2014, 30, 677–704. [Google Scholar] [CrossRef]
- Moll, G.; Ankrum, J.; Kamhieh-Milz, J.; Bieback, K.; Ringdén, O.; Volk, H.-D.; Geißler, S.; Reinke, P. Intravascular Mesenchymal Stromal/Stem Cell Therapy Product Diversification: Time for New Clinical Guidelines. Trends Mol. Med. 2019, 25, 149–163. [Google Scholar] [CrossRef] [Green Version]
- Dominici, M.; Le Blanc, K.; Mueller, I.; Slaper-Cortenbach, I.; Marini, F.; Krause, D.; Deans, R.; Keating, A.; Prockop, D.; Horwitz, E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006, 8, 315–317. [Google Scholar] [CrossRef] [PubMed]
- Hoogduijn, M.J.; Popp, F.; Verbeek, R.; Masoodi, M.; Nicolaou, A.; Baan, C.; Dahlke, M.-H. The immunomodulatory properties of mesenchymal stem cells and their use for immunotherapy. Int. Immunopharmacol. 2010, 10, 1496–1500. [Google Scholar] [CrossRef] [PubMed]
- Badiavas, A.R.; Badiavas, E.V. Potential benefits of allogeneic bone marrow mesenchymal stem cells for wound healing. Expert Opin. Biol. Ther. 2011, 11, 1447–1454. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Marfia, G.; Navone, S.E.; Di Vito, C.; Ughi, N.; Tabano, S.; Miozzo, M.; Tremolada, C.; Bolla, G.; Crotti, C.; Ingegnoli, F.; et al. Mesenchymal stem cells: Potential for therapy and treatment of chronic non-healing skin wounds. Organogenesis 2015, 11, 183–206. [Google Scholar] [CrossRef] [PubMed]
- Malhotra, P.; Shukla, M.; Meena, P.; Kakkar, A.; Khatri, N.; Nagar, R.K.; Kumar, M.; Saraswat, S.K.; Shrivastava, S.; Datt, R.; et al. Mesenchymal stem cells are prospective novel off-the-shelf wound management tools. Drug Deliv. Transl. Res. 2021, 1–26. [Google Scholar] [CrossRef]
- Falanga, V.; Iwamoto, S.; Chartier, M.; Yufit, T.; Butmarc, J.; Kouttab, N.; Shrayer, D.; Carson, P. Autologous Bone Marrow–Derived Cultured Mesenchymal Stem Cells Delivered in a Fibrin Spray Accelerate Healing in Murine and Human Cutaneous Wounds. Tissue Eng. 2007, 13, 1299–1312. [Google Scholar] [CrossRef] [PubMed]
- Kirana, S.; Stratmann, B.; Lammers, D.; Negrean, M.; Stirban, A.; Minartz, P.; Koerperich, H.; Gastens, M.H.; Götting, C.; Prohaska, W.; et al. Wound therapy with autologous bone marrow stem cells in diabetic patients with ischaemia-induced tissue ulcers affecting the lower limbs. Int. J. Clin. Pract. 2007, 61, 690–694. [Google Scholar] [CrossRef]
- Yoshikawa, T.; Mitsuno, H.; Nonaka, I.; Sen, Y.; Kawanishi, K.; Inada, Y.; Takakura, Y.; Okuchi, K.; Nonomura, A. Wound Therapy by Marrow Mesenchymal Cell Transplantation. Plast. Reconstr. Surg. 2008, 121, 860–877. [Google Scholar] [CrossRef]
- Dash, N.R.; Dash, S.; Routray, P.; Mohapatra, S.; Mohapatra, P.C. Targeting Nonhealing Ulcers of Lower Extremity in Human Through Autologous Bone Marrow-Derived Mesenchymal Stem Cells. Rejuvenation Res. 2009, 12, 359–366. [Google Scholar] [CrossRef]
- Bey, E.; Prat, M.; Duhamel, P.; Benderitter, M.; Brachet, M.; Trompier, F.; Battaglini, P.; Ernou, I.; Boutin, L.; Gourven, M.; et al. Emerging therapy for improving wound repair of severe radiation burns using local bone marrow-derived stem cell administrations. Wound Repair Regen. 2010, 18, 50–58. [Google Scholar] [CrossRef] [PubMed]
- Olmo, D.G.; Herreros, D.; De-La-Quintana, P.; Guadalajara, H.; Trébol, J.; Georgiev-Hristov, T.; Garcia-Arranz, M. Adipose-Derived Stem Cells in Crohn’s Rectovaginal Fistula. Case Rep. Med. 2010, 2010, 1–3. [Google Scholar] [CrossRef] [PubMed]
- Jain, P.; Perakath, B.; Jesudason, M.R.; Nayak, S. The effect of autologous bone marrow-derived cells on healing chronic lower extremity wounds: Results of a randomized controlled study. Ostomy Wound Manag. 2011, 57, 38. [Google Scholar]
- Marino, G.; Moraci, M.; Armenia, E.; Orabona, C.; Sergio, R.; De Sena, G.; Capuozzo, V.; Barbarisi, M.; Rosso, F.; Giordano, G.; et al. Therapy with autologous adipose-derived regenerative cells for the care of chronic ulcer of lower limbs in patients with peripheral arterial disease. J. Surg. Res. 2013, 185, 36–44. [Google Scholar] [CrossRef]
- Qin, H.L.; Zhu, X.H.; Zhang, B.; Zhou, L.; Wang, W.Y. Clinical Evaluation of Human Umbilical Cord Mesenchymal Stem Cell Transplantation After Angioplasty for Diabetic Foot. Exp. Clin. Endocrinol. Diabetes 2016, 124, 497–503. [Google Scholar] [CrossRef]
- Squillaro, T.; Peluso, G.; Galderisi, U. Clinical Trials with Mesenchymal Stem Cells: An Update. Cell Transplant. 2016, 25, 829–848. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Galderisi, U.; Peluso, G.; Di Bernardo, G. Clinical Trials Based on Mesenchymal Stromal Cells are Exponentially Increasing: Where are We in Recent Years? Stem Cell Rev. Rep. 2021, 1–14. [Google Scholar] [CrossRef]
- Lukomska, B.; Stanaszek, L.; Zuba-Surma, E.; Legosz, P.; Sarzynska, S.; Drela, K. Challenges and Controversies in Human Mesenchymal Stem Cell Therapy. Stem Cells Int. 2019, 2019, 1–10. [Google Scholar] [CrossRef] [Green Version]
- Wang, S.; Guo, L.; Ge, J.; Yu, L.; Cai, T.; Tian, R.; Jiang, Y.; Zhao, R.C.; Wu, Y. Excess Integrins Cause Lung Entrapment of Mesenchymal Stem Cells. Stem Cells 2015, 33, 3315–3326. [Google Scholar] [CrossRef] [PubMed]
- Fennema, E.M.; Tchang, L.A.; Yuan, H.; Van Blitterswijk, C.A.; Martin, I.; Scherberich, A.; De Boer, J. Ectopic bone formation by aggregated mesenchymal stem cells from bone marrow and adipose tissue: A comparative study. J. Tissue Eng. Regen. Med. 2017, 12, e150–e158. [Google Scholar] [CrossRef]
- Barkholt, L.; Flory, E.; Jekerle, V.; Lucas-Samuel, S.; Ahnert, P.; Bisset, L.; Büscher, D.; Fibbe, W.; Foussat, A.; Kwa, M.; et al. Risk of tumorigenicity in mesenchymal stromal cell–based therapies—Bridging scientific observations and regulatory viewpoints. Cytotherapy 2013, 15, 753–759. [Google Scholar] [CrossRef] [PubMed]
- Badiavas, E.V.; Abedi, M.; Butmarc, J.; Falanga, V.; Quesenberry, P. Participation of bone marrow derived cells in cutaneous wound healing. J. Cell. Physiol. 2003, 196, 245–250. [Google Scholar] [CrossRef] [PubMed]
- Pratheesh, M.D.; Gade, N.E.; Nath, A.; Dubey, P.K.; Sivanarayanan, T.B.; Madhu, D.N.; Sreekumar, T.R.; Amarpal Saikumar, G.; Sharma, G.T. Evaluation of persistence and distribution of intra-dermally administered PKH26 labelled goat bone marrow derived mesenchymal stem cells in cutaneous wound healing model. Cytotechnology 2017, 69, 841–849. [Google Scholar] [CrossRef]
- Caplan, A.I.; Correa, D. The MSC: An Injury Drugstore. Cell Stem Cell 2011, 9, 11–15. [Google Scholar] [CrossRef] [Green Version]
- Dehkordi, A.N.; Babaheydari, F.M.; Chehelgerdi, M.; Dehkordi, S.R. Skin tissue engineering: Wound healing based on stem-cell-based therapeutic strategies. Stem Cell Res. Ther. 2019, 10, 1–20. [Google Scholar] [CrossRef] [Green Version]
- Chen, L.; Tredget, E.E.; Wu, P.Y.G.; Wu, Y. Paracrine Factors of Mesenchymal Stem Cells Recruit Macrophages and Endothelial Lineage Cells and Enhance Wound Healing. PLoS ONE 2008, 3, e1886. [Google Scholar] [CrossRef] [Green Version]
- Nawaz, M.; Fatima, F.; Vallabhaneni, K.C.; Penfornis, P.; Valadi, H.; Ekström, K.; Kholia, S.; Whitt, J.D.; Fernandes, J.D.; Pochampally, R.; et al. Extracellular Vesicles: Evolving Factors in Stem Cell Biology. Stem Cells Int. 2015, 2016, 1–17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lombardi, F.; Palumbo, P.; Augello, F.R.; Cifone, M.G.; Cinque, B.; Giuliani, M. 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. 2019, 20, 3721. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Casado-Díaz, A.; Quesada-Gómez, J.M.; Dorado, G. Extracellular Vesicles Derived from Mesenchymal Stem Cells (MSC) in Regenerative Medicine: Applications in Skin Wound Healing. Front. Bioeng. Biotechnol. 2020, 8, 146. [Google Scholar] [CrossRef] [Green Version]
- An, Y.; Lin, S.; Tan, X.; Zhu, S.; Nie, F.; Zhen, Y.; Gu, L.; Zhang, C.; Wang, B.; Wei, W.; et al. Exosomes from adipose-derived stem cells and application to skin wound healing. Cell Prolif. 2021, 54, e12993. [Google Scholar] [CrossRef] [PubMed]
- Narauskaitė, D.; Vydmantaitė, G.; Rusteikaitė, J.; Sampath, R.; Rudaitytė, A.; Stašytė, G.; Calvente, M.I.A.; Jekabsone, A. Extracellular Vesicles in Skin Wound Healing. Pharmaceuticals 2021, 14, 811. [Google Scholar] [CrossRef]
- Weiliang, Z.; Lili, G. Research Advances in the Application of Adipose-Derived Stem Cells Derived Exosomes in Cutaneous Wound Healing. Ann. Dermatol. 2021, 33, 309–317. [Google Scholar] [CrossRef]
- Van Niel, G.; D’Angelo, G.; Raposo, G. Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. 2018, 19, 213–228. [Google Scholar] [CrossRef] [PubMed]
- Harding, C.; Heuser, J.; Stahl, P. Endocytosis and Intracellular Processing of Transferrin and Colloidal Gold-Transferrin in Rat Reticulocytes: Demonstration of a Pathway for Receptor Shedding. Eur. J. Cell. Biol. 1984, 35, 256–263. [Google Scholar]
- Stein, J.M.; Luzio, J.P. Ectocytosis caused by sublytic autologous complement attack on human neutrophils. The sorting of endogenous plasma-membrane proteins and lipids into shed vesicles. Biochem. J. 1991, 274, 381–386. [Google Scholar] [CrossRef]
- Hristov, M.; Erl, W.; Linder, S.; Weber, P.C. Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro. Blood 2004, 104, 2761–2766. [Google Scholar] [CrossRef] [PubMed]
- Théry, C.; Ostrowski, M.; Segura, E. Membrane vesicles as conveyors of immune responses. Nat. Rev. Immunol. 2009, 9, 581–593. [Google Scholar] [CrossRef]
- Cicero, A.L.; Stahl, P.D.; Raposo, G. Extracellular vesicles shuffling intercellular messages: For good or for bad. Curr. Opin. Cell Biol. 2015, 35, 69–77. [Google Scholar] [CrossRef]
- Pitt, J.M.; Kroemer, G.; Zitvogel, L. Extracellular vesicles: Masters of intercellular communication and potential clinical interventions. J. Clin. Investig. 2016, 126, 1139–1143. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gomzikova, M.O.; James, V.; Rizvanov, A.A. Mitochondria Donation by Mesenchymal Stem Cells: Current Understanding and Mitochondria Transplantation Strategies. Front. Cell Dev. Biol. 2021, 9, 653322. [Google Scholar] [CrossRef] [PubMed]
- Yáñez-Mó, M.; Siljander, P.R.-M.; Andreu, Z.; Zavec, A.B.; Borras, F.E.; Buzas, E.I.; Buzas, K.; Casal, E.; Cappello, F.; Carvalho, J.; et al. Biological properties of extracellular vesicles and their physiological functions. J. Extracell. Vesicles 2015, 4, 27066. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McBride, J.D.; Rodriguez-Menocal, L.; Guzman, W.; Khan, A.; Myer, C.; Liu, X.; Bhattacharya, S.K.; Badiavas, E.V. Proteomic analysis of bone marrow-derived mesenchymal stem cell extracellular vesicles from healthy donors: Implications for proliferation, angiogenesis, Wnt signaling, and the basement membrane. Stem Cell Res. Ther. 2021, 12, 1–11. [Google Scholar] [CrossRef]
- Ratajczak, J.; Miękus, K.; Kucia, M.; Zhang, J.; Reca, R.; Dvorak, P.; Ratajczak, M.Z. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: Evidence for horizontal transfer of mRNA and protein delivery. Leukemia 2006, 20, 847–856. [Google Scholar] [CrossRef] [Green Version]
- Valadi, H.; Ekström, K.; Bossios, A.; Sjöstrand, M.; Lee, J.J.; Lötvall, J. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature 2007, 9, 654–659. [Google Scholar] [CrossRef] [Green Version]
- Mittelbrunn, M.; Gutierrez-Vazquez, C.; Villarroya-Beltri, C.; González, S.; Sanchez-Cabo, F.; González, M.; Bernad, A.; Sánchez-Madrid, F. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat. Commun. 2011, 2, 282. [Google Scholar] [CrossRef] [Green Version]
- Montecalvo, A.; Larregina, A.T.; Shufesky, W.J.; Stolz, D.B.; Sullivan, M.L.G.; Karlsson, J.M.; Baty, C.J.; Gibson, G.A.; Erdos, G.; Wang, Z.; et al. Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 2012, 119, 756–766. [Google Scholar] [CrossRef] [Green Version]
- Guescini, M.; Genedani, S.; Stocchi, V.; Agnati, L.F. Astrocytes and Glioblastoma cells release exosomes carrying mtDNA. J. Neural Transm. 2009, 117, 1–4. [Google Scholar] [CrossRef] [PubMed]
- Balaj, L.; Lessard, R.; Dai, L.; Cho, Y.-J.; Pomeroy, S.L.; Breakefield, X.O.; Skog, J. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat. Commun. 2011, 2, 1–9. [Google Scholar] [CrossRef]
- Kahlert, C.; Melo, S.; Protopopov, A.; Tang, J.; Seth, S.; Koch, M.; Zhang, J.; Weitz, J.; Chin, L.; Futreal, A.; et al. Identification of Double-stranded Genomic DNA Spanning All Chromosomes with Mutated KRAS and p53 DNA in the Serum Exosomes of Patients with Pancreatic Cancer. J. Biol. Chem. 2014, 289, 3869–3875. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Thakur, B.K.; Zhang, H.; Becker, A.; Matei, I.; Huang, Y.; Costa-Silva, B.; Zheng, Y.; Hoshino, A.; Brazier, H.; Xiang, J.; et al. Double-stranded DNA in exosomes: A novel biomarker in cancer detection. Cell Res. 2014, 24, 766–769. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, X.A.; Huang, C. Tetraspanins and cell membrane tubular structures. Experientia 2012, 69, 2843–2852. [Google Scholar] [CrossRef] [PubMed]
- McBride, J.D.; Rodriguez-Menocal, L.; Guzman, W.; Candanedo, A.; Garcia-Contreras, M.; Badiavas, E.V. Bone Marrow Mesenchymal Stem Cell-Derived CD63+ Exosomes Transport Wnt3a Exteriorly and Enhance Dermal Fibroblast Proliferation, Migration, and Angiogenesis In Vitro. Stem Cells Dev. 2017, 26, 1384–1398. [Google Scholar] [CrossRef] [PubMed]
- Record, M.; Carayon, K.; Poirot, M.; Silvente-Poirot, S. Exosomes as new vesicular lipid transporters involved in cell–cell communication and various pathophysiologies. Biochim. Biophys. Acta BBA Mol. Cell Biol. Lipids 2014, 1841, 108–120. [Google Scholar] [CrossRef] [PubMed]
- Simpson, R.J.; Kalra, H.; Mathivanan, S. ExoCarta as a resource for exosomal research. J. Extracell. Vesicles 2012, 1, 18374. [Google Scholar] [CrossRef]
- Pathan, M.; Fonseka, P.; Chitti, S.V.; Kang, T.; Sanwlani, R.; Van Deun, J.; Hendrix, A.; Mathivanan, S. Vesiclepedia 2019: A compendium of RNA, proteins, lipids and metabolites in extracellular vesicles. Nucleic Acids Res. 2018, 47, D516–D519. [Google Scholar] [CrossRef] [Green Version]
- Willekens, F.L.A.; Werre, J.M.; Kruijt, J.K.; Roerdinkholder-Stoelwinder, B.; Groenen-Döpp, Y.A.M.; Bos, A.G.V.D.; Bosman, G.J.C.G.M.; Van Berkel, T.J.C. Liver Kupffer cells rapidly remove red blood cell–derived vesicles from the circulation by scavenger receptors. Blood 2005, 105, 2141–2145. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rank, A.; Nieuwland, R.; Crispin, A.; Grützner, S.; Iberer, M.; Toth, B.; Pihusch, R. Clearance of platelet microparticles in vivo. Platelets 2010, 22, 111–116. [Google Scholar] [CrossRef] [PubMed]
- Takahashi, Y.; Nishikawa, M.; Shinotsuka, H.; Matsui, Y.; Ohara, S.; Imai, T.; Takakura, Y. Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection. J. Biotechnol. 2013, 165, 77–84. [Google Scholar] [CrossRef] [PubMed]
- Chauhan, S.; Danielson, S.; Clements, V.; Edwards, N.; Ostrand-Rosenberg, S.; Fenselau, C. Surface Glycoproteins of Exosomes Shed by Myeloid-Derived Suppressor Cells Contribute to Function. J. Proteome Res. 2016, 16, 238–246. [Google Scholar] [CrossRef] [PubMed]
- Taraboletti, G.; D’Ascenzoy, S.; Giusti, I.; Marchetti, D.; Borsotti, P.; Millimaggi, D.; Giavazzi, R.; Pavan, A.; Dolo, V. Bioavailability of VEGF in Tumor-Shed Vesicles Depends on Vesicle Burst Induced by Acidic pH. Neoplasia 2006, 8, 96–103. [Google Scholar] [CrossRef] [Green Version]
- Maas, S.L.; Breakefield, X.O.; Weaver, A.M. Extracellular Vesicles: Unique Intercellular Delivery Vehicles. Trends Cell Biol. 2016, 27, 172–188. [Google Scholar] [CrossRef] [Green Version]
- Fang, S.; Xu, C.; Zhang, Y.; Xue, C.; Yang, C.; Bi, H.; Qian, X.; Wu, M.; Ji, K.; Zhao, Y.; et al. Umbilical Cord-Derived Mesenchymal Stem Cell-Derived Exosomal MicroRNAs Suppress Myofibroblast Differentiation by Inhibiting the Transforming Growth Factor-β/SMAD2 Pathway During Wound Healing. Stem Cells Transl. Med. 2016, 5, 1425–1439. [Google Scholar] [CrossRef]
- Hu, L.; Wang, J.; Zhou, X.; Xiong, Z.; Zhao, J.; Yu, R.; Huang, F.; Zhang, H.; Chen, L. Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts. Sci. Rep. 2016, 6, 32993. [Google Scholar] [CrossRef]
- Zhang, W.; Bai, X.; Zhao, B.; Li, Y.; Zhang, Y.; Li, Z.; Wang, X.; Luo, L.; Han, F.; Zhang, J.; et al. Cell-free therapy based on adipose tissue stem cell-derived exosomes promotes wound healing via the PI3K/Akt signaling pathway. Exp. Cell Res. 2018, 370, 333–342. [Google Scholar] [CrossRef]
- He, X.; Dong, Z.; Cao, Y.; Wang, H.; Liu, S.; Liao, L.; Jin, Y.; Yuan, L.; Li, B. MSC-Derived Exosome Promotes M2 Polarization and Enhances Cutaneous Wound Healing. Stem Cells Int. 2019, 2019, 1–16. [Google Scholar] [CrossRef] [Green Version]
- Ren, S.; Chen, J.; Duscher, D.; Liu, Y.; Guo, G.; Kang, Y.; Xiong, H.; Zhan, P.; Wang, Y.; Wang, C.; et al. Microvesicles from human adipose stem cells promote wound healing by optimizing cellular functions via AKT and ERK signaling pathways. Stem Cell Res. Ther. 2019, 10, 1–14. [Google Scholar] [CrossRef] [PubMed]
- Cheng, S.; Xi, Z.; Chen, G.; Liu, K.; Ma, R.; Zhou, C. Extracellular vesicle-carried microRNA-27b derived from mesenchymal stem cells accelerates cutaneous wound healing via E3 ubiquitin ligase ITCH. J. Cell. Mol. Med. 2020, 24, 11254–11271. [Google Scholar] [CrossRef]
- Jiang, L.; Zhang, Y.; Liu, T.; Wang, X.; Wang, H.; Song, H.; Wang, W. Exosomes derived from TSG-6 modified mesenchymal stromal cells attenuate scar formation during wound healing. Biochimie 2020, 177, 40–49. [Google Scholar] [CrossRef] [PubMed]
- Liu, J.; Qiu, X.; Lv, Y.; Zheng, C.; Dong, Y.; Dou, G.; Zhu, B.; Liu, A.; Wang, W.; Zhou, J.; et al. Apoptotic bodies derived from mesenchymal stem cells promote cutaneous wound healing via regulating the functions of macrophages. Stem Cell Res. Ther. 2020, 11, 1–15. [Google Scholar] [CrossRef] [PubMed]
- Qiu, X.; Liu, J.; Zheng, C.; Su, Y.; Bao, L.; Zhu, B.; Liu, S.; Wang, L.; Wang, X.; Wang, Y.; et al. Exosomes released from educated mesenchymal stem cells accelerate cutaneous wound healing via promoting angiogenesis. Cell Prolif. 2020, 53, e12830. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Han, F.; Gu, L.; Ji, P.; Yang, X.; Liu, M.; Tao, K.; Hu, D. Adipose mesenchymal stem cell exosomes promote wound healing through accelerated keratinocyte migration and proliferation by activating the AKT/HIF-1α axis. J. Mol. Histol. 2020, 51, 375–383. [Google Scholar] [CrossRef]
- Zhao, G.; Liu, F.; Liu, Z.; Zuo, K.; Wang, B.; Zhang, Y.; Han, X.; Lian, A.; Wang, Y.; Liu, M.; et al. MSC-derived exosomes attenuate cell death through suppressing AIF nucleus translocation and enhance cutaneous wound healing. Stem Cell Res. Ther. 2020, 11, 1–18. [Google Scholar] [CrossRef]
- Li, Y.; Zhang, J.; Shi, J.; Liu, K.; Wang, X.; Jia, Y.; He, T.; Shen, K.; Wang, Y.; Liu, J.; et al. Exosomes derived from human adipose mesenchymal stem cells attenuate hypertrophic scar fibrosis by miR-192-5p/IL-17RA/Smad axis. Stem Cell Res. Ther. 2021, 12, 1–16. [Google Scholar] [CrossRef]
- Wang, C.; Wang, M.; Xu, T.; Zhang, X.; Lin, C.; Gao, W.; Xu, H.; Lei, B.; Mao, C. Engineering Bioactive Self-Healing Antibacterial Exosomes Hydrogel for Promoting Chronic Diabetic Wound Healing and Complete Skin Regeneration. Theranostics 2019, 9, 65–76. [Google Scholar] [CrossRef]
- Li, B.; Luan, S.; Chen, J.; Zhou, Y.; Wang, T.; Li, Z.; Fu, Y.; Zhai, A.; Bi, C. The MSC-Derived Exosomal lncRNA H19 Promotes Wound Healing in Diabetic Foot Ulcers by Upregulating PTEN via MicroRNA-152-3p. Mol. Ther. Nucleic Acids 2019, 19, 814–826. [Google Scholar] [CrossRef]
- Shi, R.; Jin, Y.; Hu, W.; Lian, W.; Cao, C.; Han, S.; Zhao, S.; Yuan, H.; Yang, X.; Shi, J.; et al. Exosomes derived from mmu_circ_0000250-modified adipose-derived mesenchymal stem cells promote wound healing in diabetic mice by inducing miR-128-3p/SIRT1-mediated autophagy. Am. J. Physiol. Physiol. 2020, 318, C848–C856. [Google Scholar] [CrossRef] [PubMed]
- Yang, J.; Chen, Z.; Pan, D.; Li, H.; Shen, J. Umbilical Cord-Derived Mesenchymal Stem Cell-Derived Exosomes Combined Pluronic F127 Hydrogel Promote Chronic Diabetic Wound Healing and Complete Skin Regeneration. Int. J. Nanomed. 2020, 15, 5911–5926. [Google Scholar] [CrossRef]
- Pomatto, M.; Gai, C.; Negro, F.; Cedrino, M.; Grange, C.; Ceccotti, E.; Togliatto, G.; Collino, F.; Tapparo, M.; Figliolini, F.; et al. Differential Therapeutic Effect of Extracellular Vesicles Derived by Bone Marrow and Adipose Mesenchymal Stem Cells on Wound Healing of Diabetic Ulcers and Correlation to Their Cargoes. Int. J. Mol. Sci. 2021, 22, 3851. [Google Scholar] [CrossRef]
- Ti, D.; Hao, H.; Tong, C.; Liu, J.; Dong, L.; Zheng, J.; Zhao, Y.; Liu, H.; Fu, X.; Han, W. LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b. J. Transl. Med. 2015, 13, 1–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, X.; Xie, X.; Lian, W.; Shi, R.; Han, S.; Zhang, H.; Lu, L.; Li, M. Exosomes from adipose-derived stem cells overexpressing Nrf2 accelerate cutaneous wound healing by promoting vascularization in a diabetic foot ulcer rat model. Exp. Mol. Med. 2018, 50, 1–14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ding, J.; Wang, X.; Chen, B.; Zhang, J.; Xu, J. Exosomes Derived from Human Bone Marrow Mesenchymal Stem Cells Stimulated by Deferoxamine Accelerate Cutaneous Wound Healing by Promoting Angiogenesis. BioMed Res. Int. 2019, 2019, 1–12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, W.; Yu, M.; Xie, D.; Wang, L.; Ye, C.; Zhu, Q.; Liu, F.; Yang, L. Melatonin-stimulated MSC-derived exosomes improve diabetic wound healing through regulating macrophage M1 and M2 polarization by targeting the PTEN/AKT pathway. Stem Cell Res. Ther. 2020, 11, 1–15. [Google Scholar] [CrossRef]
- Yu, M.; Liu, W.; Li, J.; Lu, J.; Lu, H.; Jia, W.; Liu, F. Exosomes derived from atorvastatin-pretreated MSC accelerate diabetic wound repair by enhancing angiogenesis via AKT/eNOS pathway. Stem Cell Res. Ther. 2020, 11, 1–17. [Google Scholar] [CrossRef]
- Shafei, S.; Khanmohammadi, M.; Heidari, R.; Ghanbari, H.; Nooshabadi, V.T.; Farzamfar, S.; Akbariqomi, M.; Sanikhani, N.S.; Absalan, M.; Tavoosidana, G. Exosome loaded alginate hydrogel promotes tissue regeneration in full-thickness skin wounds: An in vivo study. J. Biomed. Mater. Res. Part A 2019, 108, 545–556. [Google Scholar] [CrossRef]
- Zhang, J.; Guan, J.; Niu, X.; Shangchun, G.; Guo, S.; Li, Q.; Xie, Z.; Zhang, C.; Wang, Y. Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. J. Transl. Med. 2015, 13, 1–14. [Google Scholar] [CrossRef] [Green Version]
- Li, X.; Liu, L.; Yang, J.; Yu, Y.; Chai, J.; Wang, L.; Ma, L.; Yin, H. Exosome Derived from Human Umbilical Cord Mesenchymal Stem Cell Mediates MiR-181c Attenuating Burn-induced Excessive Inflammation. EBioMedicine 2016, 8, 72–82. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Broughton, G.; Janis, J.; Attinger, C.E. Wound Healing: An Overview. Plast. Reconstr. Surg. 2006, 117, 1e. [Google Scholar] [CrossRef] [PubMed]
- Phillipson, M.; Kubes, P. The Healing Power of Neutrophils. Trends Immunol. 2019, 40, 635–647. [Google Scholar] [CrossRef]
- Tennenberg, S.D.; Finkenauer, R.; Dwivedi, A. Absence of Lipopolysaccharide-Induced Inhibition of Neutrophil Apoptosis in Patients with Diabetes. Arch. Surg. 1999, 134, 1229–1234. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Advani, A.; Marshall, S.M.; Thomas, T.H. Impaired neutrophil store-mediated calcium entry in Type 2 diabetes. Eur. J. Clin. Investig. 2004, 34, 43–49. [Google Scholar] [CrossRef] [PubMed]
- Taghavi-Farahabadi, M.; Mahmoudi, M.; Mahdaviani, S.A.; Baghaei, K.; Rayzan, E.; Hashemi, S.M.; Rezaei, N. Improving the function of neutrophils from chronic granulomatous disease patients using mesenchymal stem cells’ exosomes. Hum. Immunol. 2020, 81, 614–624. [Google Scholar] [CrossRef]
- Wilgus, T.A.; Roy, S.; McDaniel, J.C. Neutrophils and Wound Repair: Positive Actions and Negative Reactions. Adv. Wound Care 2013, 2, 379–388. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shojaati, G.; Khandaker, I.; Funderburgh, M.L.; Mann, M.M.; Basu, R.; Stolz, D.B.; Geary, M.L.; Dos Santos, A.; Deng, S.X.; Funderburgh, J.L. Mesenchymal Stem Cells Reduce Corneal Fibrosis and Inflammation via Extracellular Vesicle-Mediated Delivery of miRNA. Stem Cells Transl. Med. 2019, 8, 1192–1201. [Google Scholar] [CrossRef] [Green Version]
- Hesketh, M.; Sahin, K.B.; West, Z.E.; Murray, R.Z. Macrophage Phenotypes Regulate Scar Formation and Chronic Wound Healing. Int. J. Mol. Sci. 2017, 18, 1545. [Google Scholar] [CrossRef] [Green Version]
- Xie, M.; Xiong, W.; She, Z.; Wen, Z.; Abdirahman, A.S.; Wan, W.; Wen, C. Immunoregulatory Effects of Stem Cell-Derived Extracellular Vesicles on Immune Cells. Front. Immunol. 2020, 11, 13. [Google Scholar] [CrossRef] [Green Version]
- Li, J.; Xue, H.; Li, T.; Chu, X.; Xin, D.; Xiong, Y.; Qiu, W.; Gao, X.; Qian, M.; Xu, J.; et al. Exosomes derived from mesenchymal stem cells attenuate the progression of atherosclerosis in ApoE−/− mice via miR-let7 mediated infiltration and polarization of M2 macrophage. Biochem. Biophys. Res. Commun. 2019, 510, 565–572. [Google Scholar] [CrossRef]
- Zhao, J.; Li, X.; Hu, J.; Chen, F.; Qiao, S.; Sun, X.; Gao, L.; Xie, J.; Xu, B. Mesenchymal stromal cell-derived exosomes attenuate myocardial ischaemia-reperfusion injury through miR-182-regulated macrophage polarization. Cardiovasc. Res. 2019, 115, 1205–1216. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, S.; Jiang, L.; Li, H.; Shi, H.; Luo, H.; Zhang, Y.; Yu, C.; Jin, Y. Mesenchymal Stem Cells Prevent Hypertrophic Scar Formation via Inflammatory Regulation when Undergoing Apoptosis. J. Investig. Dermatol. 2014, 134, 2648–2657. [Google Scholar] [CrossRef] [Green Version]
- Fu, Y.; Sui, B.; Xiang, L.; Yan, X.; Wu, D.; Shi, S.; Hu, X. Emerging understanding of apoptosis in mediating mesenchymal stem cell therapy. Cell Death Dis. 2021, 12, 1–12. [Google Scholar] [CrossRef] [PubMed]
- Huebener, P.; Schwabe, R.F. Regulation of wound healing and organ fibrosis by toll-like receptors. Biochim. Biophys. Acta BBA Mol. Basis Dis. 2012, 1832, 1005–1017. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pukstad, B.S.; Ryan, L.; Flo, T.H.; Stenvik, J.; Moseley, R.; Harding, K.; Thomas, D.W.; Espevik, T. Non-healing is associated with persistent stimulation of the innate immune response in chronic venous leg ulcers. J. Dermatol. Sci. 2010, 59, 115–122. [Google Scholar] [CrossRef] [PubMed]
- Berlanga-Acosta, J.A.; Guillén-Nieto, G.E.; Rodríguez-Rodríguez, N.; Mendoza-Mari, Y.; Bringas-Vega, M.L.; Berlanga-Saez, J.O.; Herrera, D.G.D.B.; Martinez-Jimenez, I.; Hernandez-Gutierrez, S.; Valdés-Sosa, P.A. Cellular Senescence as the Pathogenic Hub of Diabetes-Related Wound Chronicity. Front. Endocrinol. 2020, 11. [Google Scholar] [CrossRef]
- Sanchez, M.C.; Lancel, S.; Boulanger, E.; Neviere, R. Targeting Oxidative Stress and Mitochondrial Dysfunction in the Treatment of Impaired Wound Healing: A Systematic Review. Antioxidants 2018, 7, 98. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Morrison, T.J.; Jackson, M.V.; Cunningham, E.K.; Kissenpfennig, A.; McAuley, D.; O’Kane, C.; Krasnodembskaya, A.D. Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer. Am. J. Respir. Crit. Care Med. 2017, 196, 1275–1286. [Google Scholar] [CrossRef]
- Liu, Y.; Xu, R.; Gu, H.; Zhang, E.; Qu, J.; Cao, W.; Huang, X.; Yan, H.; He, J.; Cai, Z. Metabolic reprogramming in macrophage responses. Biomark. Res. 2021, 9, 1–17. [Google Scholar] [CrossRef]
- Wang, T.; Jian, Z.; Baskys, A.; Yang, J.; Li, J.; Guo, H.; Hei, Y.; Xian, P.; He, Z.; Li, Z.; et al. MSC-derived exosomes protect against oxidative stress-induced skin injury via adaptive regulation of the NRF2 defense system. Biomaterials 2020, 257, 120264. [Google Scholar] [CrossRef]
- Li, J.; Tan, J.; Martino, M.M.; Lui, K.O. Regulatory T-Cells: Potential Regulator of Tissue Repair and Regeneration. Front. Immunol. 2018, 9, 585. [Google Scholar] [CrossRef] [PubMed]
- Zaiss, D.M.; Minutti, C.M.; Knipper, J.A. Immune- and non-immune-mediated roles of regulatory T-cells during wound healing. Immunology 2019, 157, 190–197. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Keyes, B.E.; Liu, S.; Asare, A.; Naik, S.; Levorse, J.; Polak, L.; Lu, C.; Nikolova, M.; Pasolli, H.A.; Fuchs, E. Impaired Epidermal to Dendritic T Cell Signaling Slows Wound Repair in Aged Skin. Cell 2016, 167, 1323–1338. [Google Scholar] [CrossRef] [Green Version]
- Gawronska-Kozak, B.; Bogacki, M.; Rim, J.-S.; Monroe, W.T.; Bs, J.A.M. Scarless skin repair in immunodeficient mice. Wound Repair Regen. 2006, 14, 265–276. [Google Scholar] [CrossRef] [PubMed]
- Peterson, J.M.; Barbul, A.; Breslin, R.J.; Wasserkrug, H.L.; Efron, G. Significance of T-lymphocytes in wound healing. Surgery 1987, 102. [Google Scholar]
- Reis, M.; Mavin, E.; Nicholson, L.; Green, K.; Dickinson, A.; Wang, X.-N. Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Dendritic Cell Maturation and Function. Front. Immunol. 2018, 9, 2538. [Google Scholar] [CrossRef]
- Favaro, E.; Carpanetto, A.; Caorsi, C.; Giovarelli, M.; Angelini, C.; Cavallo-Perin, P.; Tetta, C.; Camussi, G.; Zanone, M.M. Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients. Diabetologia 2015, 59, 325–333. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, K.-L.; Li, J.-Y.; Xie, G.-L.; Ma, X.-Y. Exosomes Released from Human Bone Marrow–Derived Mesenchymal Stem Cell Attenuate Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation in Mice. Front. Cell Dev. Biol. 2021, 9, 367. [Google Scholar] [CrossRef]
- Eblázquez, R.; Margallo, F.M.S.; La Rosa, O.E.; Edalemans, W.; Ãlvarez, V.; Etarazona, R.; Casado, J.G.; Blázquez, R.; Margallo, F.M.S.; La Rosa, O.E.; et al. Immunomodulatory Potential of Human Adipose Mesenchymal Stem Cells Derived Exosomes on in vitro Stimulated T Cells. Front. Immunol. 2014, 5, 556. [Google Scholar] [CrossRef] [Green Version]
- Guo, S.; DiPietro, L.A. Factors Affecting Wound Healing. J. Dent. Res. 2010, 89, 219–229. [Google Scholar] [CrossRef]
- Qing, C. The molecular biology in wound healing & non-healing wound. Chin. J. Traumatol. 2017, 20, 189–193. [Google Scholar] [CrossRef]
- Kang, T.; Jones, T.M.; Naddell, C.; Bacanamwo, M.; Calvert, J.W.; Thompson, W.E.; Bond, V.C.; Chen, Y.E.; Liu, D. Adipose-Derived Stem Cells Induce Angiogenesis via Microvesicle Transport of miRNA-31. Stem Cells Transl. Med. 2016, 5, 440–450. [Google Scholar] [CrossRef] [PubMed]
- Liang, X.; Zhang, L.; Wang, S.; Han, Q.; Zhao, R.C. Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a. J. Cell Sci. 2016, 129, 2182–2189. [Google Scholar] [CrossRef] [Green Version]
- Hoang, D.H.; Nguyen, T.D.; Nguyen, H.-P.; Nguyen, X.-H.; Do, P.T.X.; Dang, V.D.; Dam, P.T.M.; Bui, H.T.H.; Trinh, M.Q.; Vu, D.M.; et al. Differential Wound Healing Capacity of Mesenchymal Stem Cell-Derived Exosomes Originated from Bone Marrow, Adipose Tissue and Umbilical Cord Under Serum- and Xeno-Free Condition. Front. Mol. Biosci. 2020, 7, 119. [Google Scholar] [CrossRef] [PubMed]
- Zhang, B.; Wang, M.; Gong, A.; Zhang, X.; Wu, X.; Zhu, Y.; Shi, H.; Wu, L.; Zhu, W.; Qian, H.; et al. HucMSC-Exosome Mediated-Wnt4 Signaling Is Required for Cutaneous Wound Healing. Stem Cells 2014, 33, 2158–2168. [Google Scholar] [CrossRef] [PubMed]
- Kim, Y.-J.; Yoo, S.M.; Park, H.H.; Lim, H.J.; Kim, Y.-L.; Lee, S.; Seo, K.-W.; Kang, K.-S. Exosomes derived from human umbilical cord blood mesenchymal stem cells stimulates rejuvenation of human skin. Biochem. Biophys. Res. Commun. 2017, 493, 1102–1108. [Google Scholar] [CrossRef]
- Tutuianu, R.; Rosca, A.-M.; Iacomi, D.; Simionescu, M.; Titorencu, I. Human Mesenchymal Stromal Cell-Derived Exosomes Promote In Vitro Wound Healing by Modulating the Biological Properties of Skin Keratinocytes and Fibroblasts and Stimulating Angiogenesis. Int. J. Mol. Sci. 2021, 22, 6239. [Google Scholar] [CrossRef]
- Shabbir, A.; Cox, A.; Rodriguez-Menocal, L.; Salgado, M.; Van Badiavas, E. Mesenchymal Stem Cell Exosomes Induce Proliferation and Migration of Normal and Chronic Wound Fibroblasts, and Enhance Angiogenesis In Vitro. Stem Cells Dev. 2015, 24, 1635–1647. [Google Scholar] [CrossRef]
- Tooi, M.; Komaki, M.; Morioka, C.; Honda, I.; Iwasaki, K.; Yokoyama, N.; Ayame, H.; Izumi, Y.; Morita, I. Placenta Mesenchymal Stem Cell Derived Exosomes Confer Plasticity on Fibroblasts. J. Cell. Biochem. 2015, 117, 1658–1670. [Google Scholar] [CrossRef]
- Wang, Y.; Fu, B.; Sun, X.; Li, D.; Huang, Q.; Zhao, W.; Chen, X. Differentially expressed microRNAs in bone marrow mesenchymal stem cell-derived microvesicles in young and older rats and their effect on tumor growth factor-β1-mediated epithelial-mesenchymal transition in HK2 cells. Stem Cell Res. Ther. 2015, 6, 185. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Labora, J.A.F.; Morente-López, M.; Sánchez-Dopico, M.J.; Arntz, O.J.; Van De Loo, F.A.J.; De Toro, J.; Arufe, M.C. Influence of mesenchymal stem cell-derived extracellular vesicles in vitro and their role in ageing. Stem Cell Res. Ther. 2020, 11, 1–12. [Google Scholar] [CrossRef]
- Mas-Bargues, C.; Sanz-Ros, J.; Román-Domínguez, A.; Gimeno-Mallench, L.; Inglés, M.; Viña, J.; Borrás, C. Extracellular Vesicles from Healthy Cells Improves Cell Function and Stemness in Premature Senescent Stem Cells by miR-302b and HIF-1α Activation. Biomolecules 2020, 10, 957. [Google Scholar] [CrossRef] [PubMed]
- Shi, Z.; Wang, Q.; Jiang, D. Extracellular vesicles from bone marrow-derived multipotent mesenchymal stromal cells regulate inflammation and enhance tendon healing. J. Transl. Med. 2019, 17, 1–12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tan, K.T.; McGrouther, D.A.; Day, A.; Milner, C.M.; Bayat, A. Characterization of hyaluronan and TSG-6 in skin scarring: Differential distribution in keloid scars, normal scars and unscarred skin. J. Eur. Acad. Dermatol. Venereol. 2011, 25, 317–327. [Google Scholar] [CrossRef] [PubMed]
- Chandrasekaran, P.; Izadjoo, S.; Stimely, J.; Palaniyandi, S.; Zhu, X.; Tafuri, W.; Mosser, D.M. Regulatory Macrophages Inhibit Alternative Macrophage Activation and Attenuate Pathology Associated with Fibrosis. J. Immunol. 2019, 203, 2130–2140. [Google Scholar] [CrossRef]
- Hyvärinen, K.; Holopainen, M.; Skirdenko, V.; Ruhanen, H.; Lehenkari, P.; Korhonen, M.; Käkelä, R.; Laitinen, S.; Kerkelä, E. Mesenchymal Stromal Cells and Their Extracellular Vesicles Enhance the Anti-Inflammatory Phenotype of Regulatory Macrophages by Downregulating the Production of Interleukin (IL)-23 and IL-22. Front. Immunol. 2018, 9, 771. [Google Scholar] [CrossRef]
- Yeo, R.W.Y.; Lai, R.C.; Zhang, B.; Tan, S.S.; Yin, Y.; Teh, B.J.; Lim, S.K. Mesenchymal stem cell: An efficient mass producer of exosomes for drug delivery. Adv. Drug Deliv. Rev. 2013, 65, 336–341. [Google Scholar] [CrossRef]
- Zhu, J.; Lu, K.; Zhang, N.; Zhao, Y.; Ma, Q.; Shen, J.; Lin, Y.; Xiang, P.; Tang, Y.; Hu, X.; et al. Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way. Artif. Cells Nanomed. Biotechnol. 2017, 46, 1–12. [Google Scholar] [CrossRef] [Green Version]
- Ban, J.-J.; Lee, M.; Im, W.; Kim, M. Low pH increases the yield of exosome isolation. Biochem. Biophys. Res. Commun. 2015, 461, 76–79. [Google Scholar] [CrossRef]
- Thippabhotla, S.; Zhong, C.; He, M. 3D cell culture stimulates the secretion of in vivo like extracellular vesicles. Sci. Rep. 2019, 9, 1–14. [Google Scholar] [CrossRef] [Green Version]
- Ambattu, L.A.; Ramesan, S.; Dekiwadia, C.; Hanssen, E.; Li, H.; Yeo, L.Y. High frequency acoustic cell stimulation promotes exosome generation regulated by a calcium-dependent mechanism. Commun. Biol. 2020, 3, 1–9. [Google Scholar] [CrossRef]
- Fukuta, T.; Nishikawa, A.; Kogure, K. Low level electricity increases the secretion of extracellular vesicles from cultured cells. Biochem. Biophys. Rep. 2019, 21, 100713. [Google Scholar] [CrossRef] [PubMed]
- Yang, Z.; Shi, J.; Xie, J.; Wang, Y.; Sun, J.; Liu, T.; Zhao, Y.; Zhao, X.; Wang, X.; Ma, Y.; et al. Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation. Nat. Biomed. Eng. 2019, 4, 69–83. [Google Scholar] [CrossRef]
- Guo, S.; Debbi, L.; Zohar, B.; Samuel, R.; Arzi, R.S.; Fried, A.I.; Carmon, T.; Shevach, D.; Redenski, I.; Schlachet, I.; et al. Stimulating Extracellular Vesicles Production from Engineered Tissues by Mechanical Forces. Nano Lett. 2021, 21, 2497–2504. [Google Scholar] [CrossRef] [PubMed]
- Park, K.-S.; Bandeira, E.; Shelke, G.V.; Lässer, C.; Lötvall, J. Enhancement of therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. Stem Cell Res. Ther. 2019, 10, 1–15. [Google Scholar] [CrossRef]
- Haraszti, R.A.; Miller, R.; Stoppato, M.; Sere, Y.Y.; Coles, A.; Didiot, M.-C.; Wollacott, R.; Sapp, E.; Dubuke, M.L.; Li, X.; et al. Exosomes Produced from 3D Cultures of MSCs by Tangential Flow Filtration Show Higher Yield and Improved Activity. Mol. Ther. 2018, 26, 2838–2847. [Google Scholar] [CrossRef] [Green Version]
- Mendt, M.; Kamerkar, S.; Sugimoto, H.; McAndrews, K.M.; Wu, C.-C.; Gagea, M.; Yang, S.; Blanko, E.V.R.; Peng, Q.; Ma, X.; et al. Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight 2018, 3. [Google Scholar] [CrossRef]
- Labora, J.A.F.; Lesende-Rodriguez, I.; Fernández-Pernas, P.; Sangiao-Alvarellos, S.; Monserrat, L.; Arntz, O.J.; Van De Loo, F.A.J.; Mateos, J.; Arufe, M.C. Effect of age on pro-inflammatory miRNAs contained in mesenchymal stem cell-derived extracellular vesicles. Sci. Rep. 2017, 7, srep43923. [Google Scholar] [CrossRef] [Green Version]
- Lei, Q.; Liu, T.; Gao, F.; Xie, H.; Sun, L.; Zhao, A.; Ren, W.; Guo, H.; Zhang, L.; Wang, H.; et al. Microvesicles as Potential Biomarkers for the Identification of Senescence in Human Mesenchymal Stem Cells. Theranostics 2017, 7, 2673–2689. [Google Scholar] [CrossRef]
- Takasugi, M. Emerging roles of extracellular vesicles in cellular senescence and aging. Aging Cell 2018, 17, e12734. [Google Scholar] [CrossRef]
- Boulestreau, J.; Maumus, M.; Rozier, P.; Jorgensen, C.; Noël, D. Mesenchymal Stem Cell Derived Extracellular Vesicles in Aging. Front. Cell Dev. Biol. 2020, 8, 107. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, L.; Wei, J.; Ferreira, A.D.F.; Wang, H.; Zhang, L.; Zhang, Q.; Bellio, M.A.; Chu, X.-M.; Khan, A.; Jayaweera, D.; et al. Rejuvenation of Senescent Endothelial Progenitor Cells by Extracellular Vesicles Derived from Mesenchymal Stromal Cells. JACC Basic Transl. Sci. 2020, 5, 1127–1141. [Google Scholar] [CrossRef] [PubMed]
- Bai, Y.; Han, Y.-D.; Yan, X.-L.; Ren, J.; Zeng, Q.; Li, X.-D.; Pei, X.-T.; Han, Y. Adipose mesenchymal stem cell-derived exosomes stimulated by hydrogen peroxide enhanced skin flap recovery in ischemia-reperfusion injury. Biochem. Biophys. Res. Commun. 2018, 500, 310–317. [Google Scholar] [CrossRef] [PubMed]
- Zhang, H.; Liu, X.-B.; Huang, S.; Bi, X.-Y.; Wang, H.-X.; Xie, L.-X.; Wang, Y.-Q.; Cao, X.-F.; Lv, J.; Xiao, F.-J.; et al. Microvesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Stimulated by Hypoxia Promote Angiogenesis Both In Vitro and In Vivo. Stem Cells Dev. 2012, 21, 3289–3297. [Google Scholar] [CrossRef]
- Han, Y.-D.; Bai, Y.; Yan, X.-L.; Ren, J.; Zeng, Q.; Li, X.-D.; Pei, X.-T.; Han, Y. Co-transplantation of exosomes derived from hypoxia-preconditioned adipose mesenchymal stem cells promotes neovascularization and graft survival in fat grafting. Biochem. Biophys. Res. Commun. 2018, 497, 305–312. [Google Scholar] [CrossRef]
- Han, Y.; Ren, J.; Bai, Y.; Pei, X.; Han, Y. Exosomes from hypoxia-treated human adipose-derived mesenchymal stem cells enhance angiogenesis through VEGF/VEGF-R. Int. J. Biochem. Cell Biol. 2019, 109, 59–68. [Google Scholar] [CrossRef]
- Liang, B.; Liang, J.-M.; Ding, J.-N.; Xu, J.; Xu, J.-G.; Chai, Y.-M. Dimethyloxaloylglycine-stimulated human bone marrow mesenchymal stem cell-derived exosomes enhance bone regeneration through angiogenesis by targeting the AKT/mTOR pathway. Stem Cell Res. Ther. 2019, 10, 1–11. [Google Scholar] [CrossRef] [Green Version]
- Qian, X.; An, N.; Ren, Y.; Yang, C.; Zhang, X.; Li, L. Immunosuppressive Effects of Mesenchymal Stem Cells-derived Exosomes. Stem Cell Rev. Rep. 2020, 17, 411–427. [Google Scholar] [CrossRef]
- Domenis, R.; Cifù, A.; Quaglia, S.; Pistis, C.; Moretti, M.; Vicario, A.; Parodi, P.C.; Fabris, M.; Niazi, K.R.; Soon-Shiong, P.; et al. Pro inflammatory stimuli enhance the immunosuppressive functions of adipose mesenchymal stem cells-derived exosomes. Sci. Rep. 2018, 8, 1–11. [Google Scholar] [CrossRef] [PubMed]
- Harting, M.T.; Srivastava, A.; Zhaorigetu, S.; Bair, H.; Prabhakara, K.S.; Furman, N.E.T.; Vykoukal, J.V.; Ruppert, K.A.; Cox, C.S.; Olson, S.D. Inflammation-Stimulated Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Inflammation. Sstem Cells 2017, 36, 79–90. [Google Scholar] [CrossRef] [Green Version]
- Wechsler, M.E.; Rao, V.V.; Borelli, A.N.; Anseth, K.S. Engineering the MSC Secretome: A Hydrogel Focused Approach. Adv. Health Mater. 2021, 10, 2001948. [Google Scholar] [CrossRef] [PubMed]
- Santos, J.M.; Camões, S.P.; Filipe, E.; Cipriano, M.; Barcia, R.N.; Filipe, M.; Teixeira, M.; Simões, S.; Gaspar, M.; Mosqueira, D.; et al. Three-dimensional spheroid cell culture of umbilical cord tissue-derived mesenchymal stromal cells leads to enhanced paracrine induction of wound healing. Stem Cell Res. Ther. 2015, 6, 1–19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Su, N.; Gao, P.-L.; Wang, K.; Wang, J.-Y.; Zhong, Y.; Luo, Y. Fibrous scaffolds potentiate the paracrine function of mesenchymal stem cells: A new dimension in cell-material interaction. Biomaterials 2017, 141, 74–85. [Google Scholar] [CrossRef]
- Kim, M.H.; Wu, W.H.; Choi, J.H.; Kim, J.; Jun, J.H.; Ko, Y.; Lee, J.H. Galectin-1 from conditioned medium of three-dimensional culture of adipose-derived stem cells accelerates migration and proliferation of human keratinocytes and fibroblasts. Wound Repair Regen. 2017, 26, S9–S18. [Google Scholar] [CrossRef]
- Faruqu, F.N.; Liam-Or, R.; Zhou, S.; Nip, R.; Al-Jamal, K.T. Defined serum-free three-dimensional culture of umbilical cord-derived mesenchymal stem cells yields exosomes that promote fibroblast proliferation and migration in vitro. FASEB J. 2020, 35, e21206. [Google Scholar] [CrossRef]
- Yang, K.; Li, D.; Wang, M.; Xu, Z.; Chen, X.; Liu, Q.; Sun, W.; Li, J.; Gong, Y.; Liu, D.; et al. Exposure to blue light stimulates the proangiogenic capability of exosomes derived from human umbilical cord mesenchymal stem cells. Stem Cell Res. Ther. 2019, 10, 1–14. [Google Scholar] [CrossRef]
- Xu, R.; Greening, D.; Zhu, H.-J.; Takahashi, N.; Simpson, R.J. Extracellular vesicle isolation and characterization: Toward clinical application. J. Clin. Investig. 2016, 126, 1152–1162. [Google Scholar] [CrossRef] [Green Version]
- Villa, F.; Quarto, R.; Tasso, R. Extracellular Vesicles as Natural, Safe and Efficient Drug Delivery Systems. Pharmaceutics 2019, 11, 557. [Google Scholar] [CrossRef] [Green Version]
- Gandham, S.; Su, X.; Wood, J.; Nocera, A.L.; Alli, S.C.; Milane, L.; Zimmerman, A.; Amiji, M.; Ivanov, A.R. Technologies and Standardization in Research on Extracellular Vesicles. Trends Biotechnol. 2020, 38, 1066–1098. [Google Scholar] [CrossRef] [PubMed]
- Luan, X.; Sansanaphongpricha, K.; Myers, I.; Chen, H.; Yuan, H.; Sun, D. Engineering exosomes as refined biological nanoplatforms for drug delivery. Acta Pharmacol. Sin. 2017, 38, 754–763. [Google Scholar] [CrossRef] [Green Version]
- De Jong, B.; Barros, E.R.; Hoenderop, J.G.J.; Rigalli, J.P. Recent Advances in Extracellular Vesicles as Drug Delivery Systems and Their Potential in Precision Medicine. Pharmaceutics 2020, 12, 1006. [Google Scholar] [CrossRef] [PubMed]
- Gao, J.; Dong, X.; Wang, Z. Generation, purification and engineering of extracellular vesicles and their biomedical applications. Methods 2019, 177, 114–125. [Google Scholar] [CrossRef]
- Klyachko, N.L.; Arzt, C.J.; Li, S.M.; Gololobova, O.A.; Batrakova, E.V. Extracellular Vesicle-based Therapeutics: Preclinical and Clinical Investigations. Pharmaceutics 2020, 12, 1171. [Google Scholar] [CrossRef] [PubMed]
- Lara, P.; Chan, A.; Cruz, L.; Quest, A.; Kogan, M. Exploiting the Natural Properties of Extracellular Vesicles in Targeted Delivery towards Specific Cells and Tissues. Pharmaceutics 2020, 12, 1022. [Google Scholar] [CrossRef] [PubMed]
- Han, Y.; Jones, T.W.; Dutta, S.; Zhu, Y.; Wang, X.; Narayanan, S.P.; Fagan, S.C.; Zhang, D. Overview and Update on Methods for Cargo Loading into Extracellular Vesicles. Processes 2021, 9, 356. [Google Scholar] [CrossRef] [PubMed]
- Liang, Y.; Duan, L.; Lu, J.; Xia, J. Engineering exosomes for targeted drug delivery. Theranostics 2021, 11, 3183–3195. [Google Scholar] [CrossRef] [PubMed]
- Yim, N.; Ryu, S.-W.; Choi, K.; Lee, K.R.; Lee, S.; Choi, H.; Kim, J.; Shaker, M.R.; Sun, M.R.S.W.; Park, J.-H.; et al. Exosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein–protein interaction module. Nat. Commun. 2016, 7, 12277. [Google Scholar] [CrossRef]
- Ovchinnikova, L.; Terekhov, S.; Ziganshin, R.; Bagrov, D.; Filimonova, I.; Zalevsky, A.; Lomakin, Y. Reprogramming Extracellular Vesicles for Protein Therapeutics Delivery. Pharmaceutics 2021, 13, 768. [Google Scholar] [CrossRef]
- Cha, H.; Hong, S.; Park, J.H.; Park, H.H. Stem Cell-Derived Exosomes and Nanovesicles: Promotion of Cell Proliferation, Migration, and Anti-Senescence for Treatment of Wound Damage and Skin Ageing. Pharmaceutics 2020, 12, 1135. [Google Scholar] [CrossRef]
- Gangadaran, P.; Ahn, B.-C. Extracellular Vesicle- and Extracellular Vesicle Mimetics-Based Drug Delivery Systems: New Perspectives, Challenges, and Clinical Developments. Pharmaceutics 2020, 12, 442. [Google Scholar] [CrossRef]
- Del Piccolo, N.; Placone, J.; He, L.; Agudelo, S.C.; Hristova, K. Production of Plasma Membrane Vesicles with Chloride Salts and Their Utility as a Cell Membrane Mimetic for Biophysical Characterization of Membrane Protein Interactions. Anal. Chem. 2012, 84, 8650–8655. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gomzikova, M.O.; Aimaletdinov, A.M.; Bondar, O.V.; Starostina, I.G.; Gorshkova, N.V.; Neustroeva, O.A.; Kletukhina, S.K.; Kurbangaleeva, S.V.; Vorobev, V.V.; Garanina, E.E.; et al. Immunosuppressive properties of cytochalasin B-induced membrane vesicles of mesenchymal stem cells: Comparing with extracellular vesicles derived from mesenchymal stem cells. Sci. Rep. 2020, 10, 1–13. [Google Scholar] [CrossRef]
- Gomzikova, M.O.; Zhuravleva, M.N.; Vorobev, V.V.; Salafutdinov, I.I.; Laikov, A.; Kletukhina, S.K.; Martynova, E.V.; Tazetdinova, L.G.; Ntekim, A.I.; Khaiboullina, S.F.; et al. Angiogenic Activity of Cytochalasin B-Induced Membrane Vesicles of Human Mesenchymal Stem Cells. Cells 2019, 9, 95. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wu, H.; Oliver, A.E.; Ngassam, V.N.; Yee, C.K.; Parikh, A.; Yeh, Y. Preparation, characterization, and surface immobilization of native vesicles obtained by mechanical extrusion of mammalian cells. Integr. Biol. 2012, 4, 685–692. [Google Scholar] [CrossRef] [PubMed]
- Wang, L.; Abhange, K.K.; Wen, Y.; Chen, Y.; Xue, F.; Wang, G.; Tong, J.; Zhu, C.; He, X.; Wan, Y. Preparation of Engineered Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells with Ultrasonication for Skin Rejuvenation. ACS Omega 2019, 4, 22638–22645. [Google Scholar] [CrossRef] [Green Version]
- ElKhoury, K.; Koçak, P.; Kang, A.; Arab-Tehrany, E.; Ward, J.E.; Shin, S.R. Engineering Smart Targeting Nanovesicles and Their Combination with Hydrogels for Controlled Drug Delivery. Pharmaceutics 2020, 12, 849. [Google Scholar] [CrossRef]
- Lin, Y.; Wu, J.; Gu, W.; Huang, Y.; Tong, Z.; Huang, L.; Tan, J. Exosome-Liposome Hybrid Nanoparticles Deliver CRISPR/Cas9 System in MSCs. Adv. Sci. 2018, 5, 1700611. [Google Scholar] [CrossRef]
- Gimona, M.; Brizzi, M.F.; Choo, A.B.H.; Dominici, M.; Davidson, S.M.; Grillari, J.; Hermann, D.M.; Hill, A.F.; de Kleijn, D.; Lai, R.C.; et al. Critical considerations for the development of potency tests for therapeutic applications of mesenchymal stromal cell-derived small extracellular vesicles. Cytotherapy 2021, 23, 373–380. [Google Scholar] [CrossRef] [PubMed]
- Rodriguez-Menocal, L.; Salgado, M.; Ford, D.; Van Badiavas, E. Stimulation of Skin and Wound Fibroblast Migration by Mesenchymal Stem Cells Derived from Normal Donors and Chronic Wound Patients. STEM CELLS Transl. Med. 2012, 1, 221–229. [Google Scholar] [CrossRef]
- Nguyen, V.V.; Witwer, K.W.; Verhaar, M.C.; Strunk, D.; van Balkom, B.W. Functional assays to assess the therapeutic potential of extracellular vesicles. J. Extracell. Vesicles 2020, 10, e12033. [Google Scholar] [CrossRef] [PubMed]
- Li, X.; Wang, Y.; Shi, L.; Li, B.; Li, J.; Wei, Z.; Lv, H.; Wu, L.; Zhang, H.; Yang, B.; et al. Magnetic targeting enhances the cutaneous wound healing effects of human mesenchymal stem cell-derived iron oxide exosomes. J. Nanobiotechnol. 2020, 18, 1–14. [Google Scholar] [CrossRef] [PubMed]
- Patel, A.A.; Ginhoux, F.; Yona, S. Monocytes, macrophages, dendritic cells and neutrophils: An update on lifespan kinetics in health and disease. Immunology 2021, 163, 250–261. [Google Scholar] [CrossRef]
- Betzer, O.; Barnoy, E.; Sadan, T.; Elbaz, I.; Braverman, C.; Liu, Z.; Popovtzer, R. Advances in imaging strategies for in vivo tracking of exosomes. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2019, 12, e1594. [Google Scholar] [CrossRef] [PubMed]
- Li, D.; Gupta, P.; Sgaglione, N.; Grande, D. Exosomes Derived from Non-Classic Sources for Treatment of Post-Traumatic Osteoarthritis and Cartilage Injury of the Knee: In Vivo Review. J. Clin. Med. 2021, 10, 2001. [Google Scholar] [CrossRef]
- Fine, J.-D.; Bruckner-Tuderman, L.; Eady, R.A.; Bauer, E.A.; Bauer, J.W.; Has, C.; Heagerty, A.; Hintner, H.; Hovnanian, A.; Jonkman, M.F.; et al. Inherited epidermolysis bullosa: Updated recommendations on diagnosis and classification. J. Am. Acad. Dermatol. 2014, 70, 1103–1126. [Google Scholar] [CrossRef]
- Conget, P.; Rodriguez, F.; Kramer, S.; Allers, C.; Simon, V.; Palisson, F.; Gonzalez, S.; Yubero, M.J. Replenishment of type VII collagen and re-epithelialization of chronically ulcerated skin after intradermal administration of allogeneic mesenchymal stromal cells in two patients with recessive dystrophic epidermolysis bullosa. Cytotherapy 2010, 12, 429–431. [Google Scholar] [CrossRef]
- Wagner, J.E.; Ishida-Yamamoto, A.; McGrath, J.; Hordinsky, M.K.; Keene, D.R.; Woodley, D.T.; Chen, M.; Riddle, M.J.; Osborn, M.J.; Lund, T.S.; et al. Bone Marrow Transplantation for Recessive Dystrophic Epidermolysis Bullosa. N. Engl. J. Med. 2010, 363, 629–639. [Google Scholar] [CrossRef] [Green Version]
- Petrof, G.; Lwin, S.M.; Martinez-Queipo, M.; Abdul-Wahab, A.; Tso, S.; Mellerio, J.E.; Slaper-Cortenbach, I.; Boelens, J.J.; Tolar, J.; Veys, P.; et al. Potential of Systemic Allogeneic Mesenchymal Stromal Cell Therapy for Children with Recessive Dystrophic Epidermolysis Bullosa. J. Investig. Dermatol. 2015, 135, 2319–2321. [Google Scholar] [CrossRef] [Green Version]
- McBride, J.D.; Rodriguez-Menocal, L.; Candanedo, A.; Guzman, W.; Garcia-Contreras, M.; Badiavas, E.V. Dual mechanism of type VII collagen transfer by bone marrow mesenchymal stem cell extracellular vesicles to recessive dystrophic epidermolysis bullosa fibroblasts. Biochimie 2018, 155, 50–58. [Google Scholar] [CrossRef]
- Hu, S.; Li, Z.; Cores, J.; Huang, K.; Su, T.; Dinh, P.-U.; Cheng, K. Needle-Free Injection of Exosomes Derived from Human Dermal Fibroblast Spheroids Ameliorates Skin Photoaging. ACS Nano 2019, 13, 11273–11282. [Google Scholar] [CrossRef] [PubMed]
- Bartholomew, A.; Sturgeon, C.; Siatskas, M.; Ferrer, K.; McIntosh, K.; Patil, S.; Hardy, W.; Devine, S.; Ucker, D.; Deans, R.; et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp. Hematol. 2002, 30, 42–48. [Google Scholar] [CrossRef]
- Collo, G.D.; Adamo, A.; Gatti, A.; Tamellini, E.; Bazzoni, R.; Kamga, P.T.; Tecchio, C.; Quaglia, F.M.; Krampera, M. Functional dosing of mesenchymal stromal cell-derived extracellular vesicles for the prevention of acute graft-versus-host-disease. Stem Cells 2020, 38, 698–711. [Google Scholar] [CrossRef] [PubMed]
- Lener, T.; Gimona, M.; Aigner, L.; Börger, V.; Buzas, E.; Camussi, G.; Chaput, N.; Chatterjee, D.; Court, F.A.; Del Portillo, H.A.; et al. Applying extracellular vesicles based therapeutics in clinical trials–an ISEV position paper. J. Extracell. Vesicles 2015, 4, 30087. [Google Scholar] [CrossRef] [PubMed]
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Bray, E.R.; Oropallo, A.R.; Grande, D.A.; Kirsner, R.S.; Badiavas, E.V. Extracellular Vesicles as Therapeutic Tools for the Treatment of Chronic Wounds. Pharmaceutics 2021, 13, 1543. https://doi.org/10.3390/pharmaceutics13101543
Bray ER, Oropallo AR, Grande DA, Kirsner RS, Badiavas EV. Extracellular Vesicles as Therapeutic Tools for the Treatment of Chronic Wounds. Pharmaceutics. 2021; 13(10):1543. https://doi.org/10.3390/pharmaceutics13101543
Chicago/Turabian StyleBray, Eric R., Alisha R. Oropallo, Daniel A. Grande, Robert S. Kirsner, and Evangelos V. Badiavas. 2021. "Extracellular Vesicles as Therapeutic Tools for the Treatment of Chronic Wounds" Pharmaceutics 13, no. 10: 1543. https://doi.org/10.3390/pharmaceutics13101543
APA StyleBray, E. R., Oropallo, A. R., Grande, D. A., Kirsner, R. S., & Badiavas, E. V. (2021). Extracellular Vesicles as Therapeutic Tools for the Treatment of Chronic Wounds. Pharmaceutics, 13(10), 1543. https://doi.org/10.3390/pharmaceutics13101543