Abstract
Mesenchymal stem cells (MSCs) play a key role in wound healing, and the advantages
of pretreated MSCs in wound healing have previously been reported. In the present
study, we investigated the impact of LPS pretreated human adipose-derived MSCs on
skin wound healing in diabetic rats. We found that some improvements occurred through
improving angiogenesis. Then, we scrutinized the impact of lipopolysaccharide (LPS)
treatment on human adipose-derived MSCs in a high-glucose (HG) medium, as an in vitro diabetic model. In vivo findings revealed significant improvements in epithelialization and angiogenesis
of diabetic wounds which received LPS pre-MSCs. Particularly, LPS pre-MSCs-treated
diabetic wounds reached considerably higher percentages of wound closure. Also, the
granulation tissue of these wounds had higher pronounced epithelialization and more
vascularization compared with PBS-treated and MSCs-treated diabetic ones by CD31,
VEGF, CD90, collagen 1, and collagen 3 immunostaining. Western-blots analyses indicated
that LPS pre-MSCs led to the upregulation of vascular endothelial growth factor (VEGF)
and DNMT1. In addition, significantly higher cell viability (proliferation/colonie),
and elevated VEGF and DNMT1 protein expression were observed when MSCs were treated
with LPS (10 ng/ml, 6 h) in HG culture media. Based on these findings, it is suggested
that LPS pre-MSCs could promote wound repair and skin regeneration, in some major
processes, via the improvement of cellular behaviors of MSCs in the diabetic microenvironment.
The beneficial advantages of LPS treated with mesenchymal stem cells on wound healing
may lead to establishing a novel approach as an alternative therapeutic procedure
to cure chronic wounds in diabetic conditions.
Keywords
Abbreviations:
MSCs (Mesenchymal stem cells), LPS (Lipopolysaccharide), DNMT1 (DNA methyl transferase 1), HG (high-glucose), VEGF (Vascular endothelial growth factor), ECM (Extracellular matrix), HGF (Hepatocyte growth factor), bFGF (basic fibroblast growth factor), TGF-β (Transforminggrowthfactor-β), IGF-1 (Insulin-like growth factor 1)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to InjuryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Healing of chronic wounds: an update of recent developments and future possibilities.Tissue Eng Part B Rev. 2019; 25: 429-444https://doi.org/10.1089/ten.TEB.2019.0019
- Skin tissue engineering.J Biomater Sci Polym editor. 2008; 19: 955-968https://doi.org/10.1163/156856208784909417
- Angiogenesis and wound repair: when enough is enough.J Leukoc Biol. 2016; 100: 979-984https://doi.org/10.1189/jlb.4MR0316-102R
- Hopes and limits of adipose-derived stem cells (ADSCs) and mesenchymal stem cells (MSCs) in wound healing.Int J Mol Sci. 2020; 21: 1306https://doi.org/10.3390/ijms21041306
- Macrophage dysregulation and impaired skin wound healing in diabetes.Front Cell Dev Biol. 2020; 8: 528https://doi.org/10.3389/fcell.2020.00528
- Concise review: process development considerations for cell therapy.Stem Cells Transl Med. 2015; 4: 1155-1163https://doi.org/10.5966/sctm.2014-0294
- Macro-encapsulation of mesenchymal stem cells in acute and chronic liver injury animal models.J Gastroenterol Hepatol. 2021; 36: 1997-2007https://doi.org/10.1111/jgh.15434
- Acceleration of skin wound-healing reactions by autologous micrograft tissue suspension.Medicina (Kaunas). 2020; 56: 321https://doi.org/10.3390/medicina56070321
- Acceleration Mechanisms of Skin Wound Healing by Autologous Micrograft in Mice.Int J Mol Sci. 2017; 18: 1675https://doi.org/10.3390/ijms18081675
- A regenerative approach with dermal micrografts in the treatment of chronic ulcers.Stem Cell Rev Rep. 2017; 13: 139-148https://doi.org/10.1007/s12015-016-9692-2
- Stem cells in autologous microfragmented adipose tissue: current perspectives in osteoarthritis disease.Int J Mol Sci. 2021; 22: 10197https://doi.org/10.3390/ijms221910197
- And Guanbin Song. Mesenchymal stem cell migration and tissue repair.Cells. 2019; 8: 784https://doi.org/10.3390/cells8080784
- Treatment with adipose tissue-derived mesenchymal stem cells exerts anti-diabetic effects, improves long-term complications, and attenuates inflammation in type 2 diabetic rats.Stem Cell Res Ther. 2019; 10: 333https://doi.org/10.1186/s13287-019-1474-8
- Transplantation of bone marrow-derived MSCs improves cisplatinum-induced renal injury through paracrine mechanisms.Exp Mol Pathol. 2013; 94: 466-473https://doi.org/10.1016/j.yexmp.2013.03.002
- Applications of mesenchymal stem cells in skin regeneration and rejuvenation.int J Mol Sci. 2021; 22: 2410https://doi.org/10.3390/ijms22052410
- Anti-inflammatory and M2 macrophage polarization-promoting effect of mesenchymal stem cell-derived exosomes.Int Immunopharmacol. 2021; 97107823https://doi.org/10.1016/j.intimp.2021.107823
- Paracrine Mechanisms of Mesenchymal Stromal Cells in Angiogenesis.Stem Cells Int. 2020; 20204356359https://doi.org/10.1155/2020/4356359
- Effects of mesenchymal stem cell-derived paracrine signals and their delivery strategies.Adv Healthc Mater. 2021; 10e2001689https://doi.org/10.1002/adhm.202001689
- Mechanisms of modulation and differentiation in mesenchymal stem/stromal cells.Stem Cells. 2021; 39: 1-2https://doi.org/10.1002/stem.3321
- Human marrow-derived mesenchymal stromal cells decrease cisplatin renotoxicity in vitro and in vivo and enhance survival of mice post-intraperitoneal injection.Am J Physiol Renal Physiol. 2010; 299: F1288-F1298https://doi.org/10.1152/ajprenal.00671.2009
- Intramuscular injection of human umbilical cord-derived mesenchymal stem cells improves cardiac function in dilated cardiomyopathy rats.Stem Cell Res Ther. 2017; 8: 18https://doi.org/10.1186/s13287-017-0472-y
- Efficacy of topical and systemic transplantation of mesenchymal stem cells in a rat model of diabetic ischemic wounds.Stem Cell Res Ther. 2021; 12: 220https://doi.org/10.1186/s13287-021-02288-8
- Hypoxia pretreatment of bone marrow-derived mesenchymal stem cells seeded in a collagen-chitosan sponge scaffold promotes skin wound healing in diabetic rats with hindlimb ischemia.Wound Repair Regen. 2016; 24: 45-56https://doi.org/10.1111/wrr.12369
- Mesenchymal stromal cell-derived extracellular vesicles in the treatment of diabetic foot ulcers: application and challenges.Stem Cell Rev Rep. 2021; 17: 369-378https://doi.org/10.1007/s12015-020-10014-9
- Increased expression of EGR-1 in diabetic human adipose tissue-derived mesenchymal stem cells reduces their wound healing capacity.Stem Cells Dev. 2016; 25: 760-773https://doi.org/10.1089/scd.2015.0335
- Mesenchymal stromal cells form vascular tubes when placed in fibrin sealant and accelerate wound healing in vivo.Biomaterials. 2015; 40: 61-71https://doi.org/10.1016/j.biomaterials.2014.11.011
- Therapeutic strategies for IVD Regeneration through Hyaluronan/SDF-1-Based Hydrogel and Intravenous Administration of MSCs.Int J Mol Sci. 2021; 22: 9609https://doi.org/10.3390/ijms22179609
- Multimodal Assessment of Mesenchymal Stem Cell Therapy for Diabetic Vascular Complications.Theranostics. 2017; 7: 3876-3888https://doi.org/10.7150/thno.19547
- Angiogenic effect of mesenchymal stem cells as a therapeutic target for enhancing diabetic wound healing.Int J Low Extrem Wounds. 2014; 13: 88-93https://doi.org/10.1177/1534734614534977
- Placenta mesenchymal stem cell accelerates wound healing by enhancing angiogenesis in diabetic Goto-Kakizaki (GK) rats.Biochem Biophys Res Commun. 2013; 438: 410-419https://doi.org/10.1016/j.bbrc.2013.07.088
- Time-dependent LPS exposure commands MSC immunoplasticity through TLR4 activation leading to opposite therapeutic outcome in EAE.Stem Cell Res Ther. 2020; 11: 416https://doi.org/10.1186/s13287-020-01840-2
- Constitutive and LPS-stimulated secretome of porcine Vascular Wall-Mesenchymal Stem Cells exerts effects on in vitro endothelial angiogenesis.BMC Vet Res. 2019; 15: 123https://doi.org/10.1186/s12917-019-1873-1
- Antimicrobial effects of mesenchymal stem cells primed by modified LPS on bacterial clearance in sepsis.J Cell Physiol. 2019; 234: 4970-4986https://doi.org/10.1002/jcp.27298
- Preconditioning of bone marrow-derived mesenchymal stem cells highly strengthens their potential to promote IL-6-dependent M2b polarization.Stem Cell Res Ther. 2018; 9: 286https://doi.org/10.1186/s13287-018-1039-2
- Xinxing Wan, Zhaohui Mo. c-Jun overexpression accelerates wound healing in diabetic rats by human umbilical cord-derived mesenchymal stem cells.Stem Cells Int. 2020; 20207430968https://doi.org/10.1155/2020/7430968
- The effects of dosage and the routes of administrations of streptozotocin and alloxan on induction rate of type1 diabetes mellitus and mortality rate in rats.Lab Anim Res. 2016; 32: 160-165https://doi.org/10.5625/lar.2016.32.3.160
- The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression.Oncogene. 2008; 27: 2187-2197https://doi.org/10.1038/sj.onc.1210855
- LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b.J Transl Med. 2015; 13: 308https://doi.org/10.1186/s12967-015-0642-6
- Polyphenols as potential enhancers of stem cell therapy against neurodegeneration.Neural Regen Res. 2022; 17: 2093-2101https://doi.org/10.4103/1673-5374.335826
- Magnet-targeted delivery of bone marrow-derived mesenchymal stem cells improves therapeutic efficacy following hypoxic-ischemic brain injury.Neural Regen Res. 2021; 16: 2324-2329https://doi.org/10.4103/1673-5374.310942
- Insights into stem cell therapy for diabetic retinopathy: a bibliometric and visual analysis.Neural Regen Res. 2021; 16: 172-178https://doi.org/10.4103/1673-5374.286974
- Exosomes derived from human umbilical cord mesenchymal stem cells enhance insulin sensitivity in insulin resistant human adipocytes.Curr Med Sci. 2021; 41: 87-93https://doi.org/10.1007/s11596-021-2323-4
- Induction of differentiation of mesenchymal stem cells into retinal pigment epithelial cells for retinal regeneration by using ciliary neurotrophic factor in diabetic rats.Curr Med Sci. 2021; 41: 145-152https://doi.org/10.1007/s11596-021-2329-y
- Mesenchymal stem cells coated by the extracellular matrix promote wound healing in diabetic rats.Stem Cells Int. 2019; 20199564869https://doi.org/10.1155/2019/9564869
- Mesenchymal stem cells for chronic wound healing: current status of preclinical and clinical studies.Tissue Eng Part B Rev. 2020; 26: 555-570https://doi.org/10.1089/ten.TEB.2019.0351
- MSCs rescue impaired wound healing in a murine LAD1 model by adaptive responses to low TGF-β1 levels.EMBO Rep. 2020; 21: e49115https://doi.org/10.15252/embr.201949115
- Epidermal stem cells (ESCs) accelerate diabetic wound healing via the Notch signalling pathway.Biosci. Rep. 2016; 36: e00364https://doi.org/10.1042/BSR20160034
- Targeting programmed cell death to improve stem cell therapy: implications for treating diabetes and diabetes-related diseases.Front Cell Dev Biol. 2021; 9809656https://doi.org/10.3389/fcell.2021.809656
- Mesenchymal stem cell-derived extracellular vesicles for skin wound healing.Adv Exp Med Biol. 2021; 1310: 495-507https://doi.org/10.1007/978-981-33-6064-8_18
- Mesenchymal stem cells and cutaneous wound healing: novel methods to increase cell delivery and therapeutic efficacy.Stem Cell Res Ther. 2016; 7: 37https://doi.org/10.1186/s13287-016-0303-6
- Mesenchymal stem cells: the roles and functions in cutaneous wound healing and tumor growth.J Dermatol Sci. 2017; 86: 83-89https://doi.org/10.1016/j.jdermsci.2016.11.005
- Mesenchymal stromal cells pretreated with pro-inflammatory cytokines promote skin wound healing through VEGFC-mediated angiogenesis.Stem Cells Transl Med. 2020; 9: 1218-1232https://doi.org/10.1002/sctm.19-0241
- Transplantation of photobiomodulation-preconditioned diabetic stem cells accelerates ischemic wound healing in diabetic rats.Stem Cell Res Ther. 2020; 11: 494https://doi.org/10.1186/s13287-020-01967-2
- Epidermal stem cells in wound healing and their clinical applications.Stem Cell Res Ther. 2019; 10: 229https://doi.org/10.1186/s13287-019-1312-z
- Novel trends in application of stem cells in skin wound healing.Eur J Pharmacol. 2019; 843: 307-315https://doi.org/10.1016/j.ejphar.2018.12.012
- Acceleration of wound healing with stem cell-derived growth factors.Int J Oral Maxillofac Implants. 2013; 28: e369-e375https://doi.org/10.11607/jomi.te17
- Autophagy promotes MSC-mediated vascularization in cutaneous wound healing via regulation of VEGF secretion.Cell Death Dis. 2018; 9: 58https://doi.org/10.1038/s41419-017-0082-8
- TNF-α and IL-1β-activated human mesenchymal stromal cells increase airway epithelial wound healing in vitro via activation of the epidermal growth factor receptor.Respir Res. 2016; 17: 3https://doi.org/10.1186/s12931-015-0316-1
- Mesenchymal stem cells' interaction with skin: wound-healing effect on fibroblast cells and skin tissue.Wound Repair Regen. 2010; 18: 655-661https://doi.org/10.1111/j.1524-475X.2010.00636.x
- Comparison of human umbilical cord blood-derived mesenchymal stem cells with healthy fibroblasts on wound-healing activity of diabetic fibroblasts.Int Wound J. 2018; 15: 133-139https://doi.org/10.1111/iwj.12849
- Bone Marrow-Derived Mesenchymal Stem Cells Promoted Cutaneous Wound Healing by Regulating Keratinocyte Migration via β 2-Adrenergic Receptor Signaling.Mol Pharm. 2018; 15: 2513-2527https://doi.org/10.1021/acs.molpharmaceut.7b01138
- Concise review: role of mesenchymal stem cells in wound repair.Stem Cells Transl Med. 2012; 1: 142-149https://doi.org/10.5966/sctm.2011-0018
- Neurotrophin-3 accelerates wound healing in diabetic mice by promoting a paracrine response in mesenchymal stem cells.Cell Transplant. 2013; 22: 1011-1021https://doi.org/10.3727/096368912x657495
- Effects of human umbilical cord blood-derived mesenchymal stromal cells and dermal fibroblasts on diabetic wound healing.Cytotherapy. 2017; 19: 821-828https://doi.org/10.1016/j.jcyt.2017.03.074
- Progress in studies of epidermal stem cells and their application in skin tissue engineering.Stem Cell Res Ther. 2020; 11: 303https://doi.org/10.1186/s13287-020-01796-3
- Mesenchymal Stem Cells Promote Diabetic Corneal Epithelial Wound Healing Through TSG-6-Dependent Stem Cell Activation and Macrophage Switch.Invest Ophthalmol Vis Sci. 2017; 58: 4344-4354https://doi.org/10.1167/iovs.17-21506
- Paracrine action of mesenchymal stromal cells delivered by microspheres contributes to cutaneous wound healing and prevents scar formation in mice.Cytotherapy. 2015; 17: 922-931https://doi.org/10.1016/j.jcyt.2015.03.690
- Epidermal stem cells in wound healing and their clinical applications.Stem Cell Res Ther. 2019; 10: 229https://doi.org/10.1186/s13287-019-1312-z
- A systematic summary of survival and death signalling during the life of hair follicle stem cells.Stem Cell Res Ther. 2021; 12: 453https://doi.org/10.1186/s13287-021-02527-y
- Drilling combined with adipose-derived stem cells and bone morphogenetic protein-2 to treat femoral head epiphyseal necrosis in juvenile rabbits.Current Medical Science. 2018; 38: 277-288https://doi.org/10.1007/s11596-018-1876-3
- Wee Keng Lim, Seng Teik Lee, Alvin Wen Choong Chua. In vitro characterization of human hair follicle dermal sheath mesenchymal stromal cells and their potential in enhancing diabetic wound healing.Cytotherapy. 2015; 17: 1036-1051https://doi.org/10.1016/j.jcyt.2015.04.001
- Adipose tissue derived mesenchymal stem cell (AD-MSC) promotes skin wound healing in diabetic rats.Diabetes Res Clin Pract. 2011; 93: 228-234https://doi.org/10.1016/j.diabres.2011.04.018
- Effects of nanofiber/stem cell composite on wound healing in acute full-thickness skin wounds.Tissue Eng Part A. 2011; 17: 1413-1424https://doi.org/10.1089/ten.TEA.2010.0373
- Enhanced wound-healing quality with bone marrow mesenchymal stem cells autografting after skin injury.Wound Repair Regen. 2006; 14: 325-335https://doi.org/10.1111/j.1743-6109.2006.00128.x
- Efficacy assessment of mesenchymal stem cell transplantation for burn wounds in animals: a systematic review.Stem Cell Res Ther. 2020; 11: 372https://doi.org/10.1186/s13287-020-01879-1
- Prakash Chandra Mohapatra. Towards reaching the target: clinical application of mesenchymal stem cells for diabetic foot ulcers.Rejuvenation Res. 2014; 17: 40-53https://doi.org/10.1089/rej.2013.1467
- Adipose-Derived Mesenchymal Stromal Cells in Regenerative Medicine: state of Play, Current Clinical Trials, and Future Prospects.Adv Wound Care (New Rochelle). 2021; 10: 24-48https://doi.org/10.1089/wound.2020.1175
- Three-dimensional graphene foams loaded with bone marrow derived mesenchymal stem cells promote skin wound healing with reduced scarring.Mater Sci Eng C Mater Biol Appl. 2015; 57: 181-188https://doi.org/10.1016/j.msec.2015.07.062
- Mechanisms of action of mesenchymal stem cells in cutaneous wound repair and regeneration.Cell Tissue Res. 2012; 348: 371-377https://doi.org/10.1007/s00441-012-1393-9
- Melatonin enhances the human mesenchymal stem cells motility via melatonin receptor 2 coupling with Gαq in skin wound healing.J Pineal Res. 2014; 57: 393-407https://doi.org/10.1111/jpi.12179
- Porphyromonas gingivalis lipopolysaccharides regulate functions of bone marrow mesenchymal stem cells.Cell Prolif. 2015; 48: 239-248https://doi.org/10.1111/cpr.12173
- Impact of bacteria and bacterial components on osteogenic and adipogenic differentiation of adipose-derived mesenchymal stem cells.Exp Cell Res. 2013; 319: 2883-2892https://doi.org/10.1016/j.yexcr.2013.08.020
- Mesenchymal stem cells and skin wound repair and regeneration: possibilities and questions.Cell Tissue Res. 2009; 335: 317-321https://doi.org/10.1007/s00441-008-0724-3
- Talita da Silva Jeremias, Andrea Gonçalves Trentin. In vitro comparative study of human mesenchymal stromal cells from dermis and adipose tissue for application in skin wound healing.J Tissue Eng Regen Med. 2019; 13: 729-741https://doi.org/10.1002/term.2820
- Platelet-derived respiratory-competent mitochondria transfer to mesenchymal stem cells to promote wound healing via metabolic reprogramming.Platelets. 2022; 33: 171-173https://doi.org/10.1080/09537104.2021.1961717
- Stem cells and growth factors-based delivery approaches for chronic wound repair and regeneration: a promise to heal from within.Life Sci. 2021; 268118932https://doi.org/10.1016/j.lfs.2020.118932
- Tissue regeneration: the crosstalk between mesenchymal stem cells and immune response.Cell Immunol. 2018; 326: 86-93https://doi.org/10.1016/j.cellimm.2017.11.010
- IL-7 overexpression enhances therapeutic potential of rat bone marrow mesenchymal stem cells for diabetic wounds.Cell Immunol. 2018; 326: 86-93https://doi.org/10.1111/wrr.12706
- Adult bone-marrow-derived mesenchymal stem cells contribute to wound healing of skin appendages.Cell Tissue Res. 2006; 326: 725-736https://doi.org/10.1007/s00441-006-0270-9
- Secretion of SDF-1alpha by bone marrow-derived stromal cells enhances skin wound healing of C57BL/6 mice exposed to ionizing radiation.J Cell Mol Med. 2010; 14: 1594-1604https://doi.org/10.1111/j.1582-4934.2009.00887.x
- Tunable hydrogels for mesenchymal stem cell delivery: integrin-induced transcriptome alterations and hydrogel optimization for human wound healing.Stem Cells. 2020; 38: 231-245https://doi.org/10.1002/stem.3105
- Role of mesenchymal stem cells in dermal repair in burns and diabetic wounds.Curr Stem Cell Res Ther. 2017; 12: 61-70https://doi.org/10.2174/1574888x11666160714115926
- Human gingiva-derived mesenchymal stem cells elicit polarization of m2 macrophages and enhance cutaneous wound healing.Stem Cells. 2010; 28: 1856-1868https://doi.org/10.1002/stem.503
- Evaluation of canine bone marrow-derived mesenchymal stem cells for experimental full-thickness cutaneous wounds in a diabetic rat model.Expert Opin Biol Ther. 2021; 21: 1655-1664https://doi.org/10.1080/14712598.2022.1990260
- Stem cell transplantation in the treatment of type 1 diabetes mellitus: from insulin replacement to beta cells replacement.Front Endocrinol (Lausanne). 2022; 13859638https://doi.org/10.3389/fendo.2022.859638
- Programmed cell death in stem cell-based therapy: mechanisms and clinical applications.World J Stem Cells. 2021; 13: 386-415https://doi.org/10.4252/wjsc.v13.i5.386
- Conditioned medium from induced pluripotent stem cell-derived mesenchymal stem cells accelerates cutaneous wound healing through enhanced angiogenesis.Stem Cell Res Ther. 2021; 12: 295https://doi.org/10.1186/s13287-021-02366-x
- Mesenchymal stem cell-conditioned media: a novel alternative of stem cell therapy for quality wound healing.J Cell Physiol. 2020; 235: 5555-5569https://doi.org/10.1002/jcp.29486
- Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis.Stem Cells. 2007; 25: 2648-2659https://doi.org/10.1634/stemcells.2007-0226
- Mesenchymal stem cells modified with angiopoietin-1 gene promote wound healing.Stem Cell Res Ther. 2013; 4: 113https://doi.org/10.1186/scrt324
Article info
Publication history
Published online: September 24, 2022
Accepted:
September 23,
2022
Identification
Copyright
© 2022 Published by Elsevier Ltd.