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Angiogenin Released from ABCB5+ Stromal Precursors Improves Healing of Diabetic Wounds by Promoting Angiogenesis

  • Author Footnotes
    Contributed equally first authors
    Karmveer Singh
    Footnotes
    Contributed equally first authors
    Affiliations
    Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
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  • Author Footnotes
    Contributed equally first authors
    Pallab Maity
    Footnotes
    Contributed equally first authors
    Affiliations
    Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
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  • Albert Kallon Koroma
    Affiliations
    Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
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  • Abhijit Basu
    Affiliations
    Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
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  • Author Footnotes
    § Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive, Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
    Rajeev Kumar Pandey
    Footnotes
    § Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive, Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
    Affiliations
    Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
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  • Author Footnotes
    ‡ Current address: Bredent medical GmbH & Co.KG, Senden, Germany.
    Seppe Vander Beken
    Footnotes
    ‡ Current address: Bredent medical GmbH & Co.KG, Senden, Germany.
    Affiliations
    Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
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  • Philipp Haas
    Affiliations
    Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
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  • Linda Krug
    Affiliations
    Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
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  • Adelheid Hainzl
    Affiliations
    Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
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  • Anca Sindrilaru
    Affiliations
    Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
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  • Christiane Pfeiffer
    Affiliations
    Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
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  • Meinhard Wlaschek
    Affiliations
    Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
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  • Natasha Y. Frank
    Affiliations
    Transplantation Research Center, Boston Children's Hospital and Brigham and Women’s Hospital, Boston, MA, USA

    Department of Medicine, Boston VA Healthcare System, West Roxbury, MA, USA

    Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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  • Markus H. Frank
    Affiliations
    Transplantation Research Center, Boston Children's Hospital and Brigham and Women’s Hospital, Boston, MA, USA

    Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Transplantation Research Center, Boston Children’s Hospital and Brigham and Women’s Hospital, Boston, MA, USA

    Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA

    School of Medical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia
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  • Christoph Ganss
    Affiliations
    TICEBA GmbH, Heidelberg, Germany

    RHEACELL GmbH & Co. KG, Heidelberg, Germany
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  • András Bánvölgyi
    Affiliations
    Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary
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  • Norbert Wikonkál
    Affiliations
    Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary
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  • Sabine Eming
    Affiliations
    Department of Dermatology and Venereology, University of Cologne, Cologne, Germany
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  • Irena Pastar
    Affiliations
    Wound Healing and Regenerative Medicine Research Program, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA
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  • Marjana Tomic-Canic
    Affiliations
    Wound Healing and Regenerative Medicine Research Program, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA
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  • Author Footnotes
    # contributed equally senior authors
    Mark A. Kluth
    Footnotes
    # contributed equally senior authors
    Affiliations
    TICEBA GmbH, Heidelberg, Germany

    RHEACELL GmbH & Co. KG, Heidelberg, Germany
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  • Author Footnotes
    # contributed equally senior authors
    Karin Scharffetter-Kochanek
    Correspondence
    Corresponding author: Karin Scharffetter-Kochanek, M.D, Department of Dermatology and Allergic Diseases, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany. Telephone: 49-731-5005-7501; Fax: 49-731-5005-7502
    Footnotes
    # contributed equally senior authors
    Affiliations
    Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany
    Search for articles by this author
  • Author Footnotes
    ‡ Current address: Bredent medical GmbH & Co.KG, Senden, Germany.
    § Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive, Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
    Contributed equally first authors
    # contributed equally senior authors
Published:November 19, 2021DOI:https://doi.org/10.1016/j.jid.2021.10.026

      Abstract

      Severe angiopathy is a major driver for diabetes associated secondary complications. Knowledge on underlying mechanisms essential for advanced therapies to attenuate these pathologies is limited. Injection of ABCB5+ stromal precursors (SPs) at the edge of non-healing diabetic wounds in a murine db/db model, closely mirroring human type II diabetes, profoundly accelerates wound closure. Strikingly, enhanced angiogenesis was substantially enforced by the release of the ribonuclease angiogenin from ABCB5+ SPs. This compensates for the profoundly reduced angiogenin expression in non-treated murine chronic diabetic wounds. Silencing of angiogenin in ABCB5+ SPs prior to injection significantly reduced angiogenesis and delayed wound closure in diabetic db/db mice implying an unprecedented key role for angiogenin in tissue regeneration in diabetes. These data hold significant promise for further refining SPs-based therapies of non-healing diabetic foot ulcers and other pathologies with impaired angiogenesis.

      Graphical abstract

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      References

        • Aldworth J.
        • Patterson C.
        • Jacobs E.
        • Misra A.
        • Tamayo T.
        • Snouffer E.
        • et al.
        IDF DIABETES ATLAS.
        International Diabetes Federation. 2017; : 150
        • Armstrong D.G.
        • Swerdlow M.A.
        • Armstrong A.A.
        • Conte M.S.
        • Padula W.V.
        • Bus S.A.
        Five year mortality and direct costs of care for people with diabetic foot complications are comparable to cancer.
        J Foot Ankle Res. 2020; 13: 16
        • Augustin M.
        • Vanscheidt W.
        Chronic venous leg ulcers: the future of cell-based therapies.
        Lancet (London, England). 2012; 380: 953-955
        • Chen H.
        • Charlat O.
        • Tartaglia L.A.
        • Woolf E.A.
        • Weng X.
        • Ellis S.J.
        • et al.
        Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice.
        Cell. 1996; 84: 491-495
        • Cho S.
        • Beintema J.J.
        • Zhang J.
        The ribonuclease A superfamily of mammals and birds: identifying new members and tracing evolutionary histories.
        Genomics. 2005; 85: 208-220
        • Davey G.C.
        • Patil S.B.
        • O'Loughlin A.
        • O'Brien T.
        Mesenchymal stem cell-based treatment for microvascular and secondary complications of diabetes mellitus.
        Frontiers in endocrinology. 2014; 5: 86
        • Ferguson R.
        • Subramanian V.
        The cellular uptake of angiogenin, an angiogenic and neurotrophic factor is through multiple pathways and largely dynamin independent.
        PloS one. 2018; 13e0193302
        • Goncalves K.A.
        • Silberstein L.
        • Li S.
        • Severe N.
        • Hu M.G.
        • Yang H.
        • et al.
        Angiogenin Promotes Hematopoietic Regeneration by Dichotomously Regulating Quiescence of Stem and Progenitor Cells.
        Cell. 2016; 166: 894-906
        • Greenway M.J.
        • Andersen P.M.
        • Russ C.
        • Ennis S.
        • Cashman S.
        • Donaghy C.
        • et al.
        ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis.
        Nat Genet. 2006; 38: 411-413
        • Holz M.K.
        • Ballif B.A.
        • Gygi S.P.
        • Blenis J.
        mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events.
        Cell. 2005; 123: 569-580
        • Ibaragi S.
        • Yoshioka N.
        • Kishikawa H.
        • Hu J.K.
        • Sadow P.M.
        • Li M.
        • et al.
        Angiogenin-stimulated rRNA transcription is essential for initiation and survival of AKT-induced prostate intraepithelial neoplasia.
        Molecular cancer research : MCR. 2009; 7: 415-424
        • Jiang D.
        • Qi Y.
        • Walker N.G.
        • Sindrilaru A.
        • Hainzl A.
        • Wlaschek M.
        • et al.
        The effect of adipose tissue derived MSCs delivered by a chemically defined carrier on full-thickness cutaneous wound healing.
        Biomaterials. 2013; 34: 2501-2515
        • Kim Y.N.
        • Kim D.H.
        Decreased serum angiogenin level in Alzheimer's disease.
        Progress in neuro-psychopharmacology & biological psychiatry. 2012; 38: 116-120
        • Kishimoto K.
        • Liu S.
        • Tsuji T.
        • Olson K.A.
        • Hu G.F.
        Endogenous angiogenin in endothelial cells is a general requirement for cell proliferation and angiogenesis.
        Oncogene. 2005; 24: 445-456
        • Koliaraki V.
        • Prados A.
        • Armaka M.
        • Kollias G.
        The mesenchymal context in inflammation, immunity and cancer.
        Nature immunology. 2020; 21: 974-982
        • Meyer P.
        • Maity P.
        • Burkovski A.
        • Schwab J.
        • Mussel C.
        • Singh K.
        • et al.
        A model of the onset of the senescence associated secretory phenotype after DNA damage induced senescence.
        PLoS Comput Biol. 2017; 13e1005741
        • Okonkwo U.A.
        • Chen L.
        • Ma D.
        • Haywood V.A.
        • Barakat M.
        • Urao N.
        • et al.
        Compromised angiogenesis and vascular Integrity in impaired diabetic wound healing.
        PloS one. 2020; 15e0231962
        • Qi Y.
        • Jiang D.
        • Sindrilaru A.
        • Stegemann A.
        • Schatz S.
        • Treiber N.
        • et al.
        TSG-6 released from intradermally injected mesenchymal stem cells accelerates wound healing and reduces tissue fibrosis in murine full-thickness skin wounds.
        The Journal of investigative dermatology. 2014; 134: 526-537
        • Ressler S.
        • Bartkova J.
        • Niederegger H.
        • Bartek J.
        • Scharffetter-Kochanek K.
        • Jansen-Durr P.
        • et al.
        p16INK4A is a robust in vivo biomarker of cellular aging in human skin.
        Aging Cell. 2006; 5: 379-389
        • Riordan J.F.
        Angiogenin. Methods in enzymology. 2001; 341: 263-273
        • Schatton T.
        • Yang J.
        • Kleffel S.
        • Uehara M.
        • Barthel S.R.
        • Schlapbach C.
        • et al.
        ABCB5 Identifies Immunoregulatory Dermal Cells.
        Cell Rep. 2015; 12: 1564-1574
        • Shahbazian D.
        • Roux P.P.
        • Mieulet V.
        • Cohen M.S.
        • Raught B.
        • Taunton J.
        • et al.
        The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity.
        EMBO J. 2006; 25: 2781-2791
        • Shao J.
        • Yamashita H.
        • Qiao L.
        • Friedman J.E.
        Decreased Akt kinase activity and insulin resistance in C57BL/KsJ-Leprdb/db mice.
        J Endocrinol. 2000; 167: 107-115
        • Shapiro R.
        • Strydom D.J.
        • Olson K.A.
        • Vallee B.L.
        Isolation of angiogenin from normal human plasma.
        Biochemistry. 1987; 26: 5141-5146
        • Siebert J.
        • Reiwer-Gostomska M.
        • Mysliwska J.
        • Marek N.
        • Raczynska K.
        • Glasner L.
        Glycemic control influences serum angiogenin concentrations in patients with type 2 diabetes.
        Diabetes Care. 2010; 33: 1829-1830
        • Silberstein L.
        • Goncalves K.A.
        • Kharchenko P.V.
        • Turcotte R.
        • Kfoury Y.
        • Mercier F.
        • et al.
        Proximity-Based Differential Single-Cell Analysis of the Niche to Identify Stem/Progenitor Cell Regulators.
        Cell stem cell. 2016; 19: 530-543
        • Singh K.
        • Krug L.
        • Basu A.
        • Meyer P.
        • Treiber N.
        • Vander Beken S.
        • et al.
        Alpha-Ketoglutarate Curbs Differentiation and Induces Cell Death in Mesenchymal Stromal Precursors with Mitochondrial Dysfunction.
        Stem cells (Dayton, Ohio). 2017; 35: 1704-1718
        • Soria-Juan B.
        • Escacena N.
        • Capilla-Gonzalez V.
        • Aguilera Y.
        • Llanos L.
        • Tejedo J.R.
        • et al.
        Cost-Effective, Safe, and Personalized Cell Therapy for Critical Limb Ischemia in Type 2 Diabetes Mellitus.
        Front Immunol. 2019; 10: 1151
        • Steidinger T.U.
        • Standaert D.G.
        • Yacoubian T.A.
        A neuroprotective role for angiogenin in models of Parkinson's disease.
        Journal of neurochemistry. 2011; 116: 334-341
        • Tahergorabi Z.
        • Khazaei M.
        Imbalance of angiogenesis in diabetic complications: the mechanisms.
        Int J Prev Med. 2012; 3: 827-838
        • Tappenbeck N.
        • Schroder H.M.
        • Niebergall-Roth E.
        • Hassinger F.
        • Dehio U.
        • Dieter K.
        • et al.
        In vivo safety profile and biodistribution of GMP-manufactured human skin-derived ABCB5-positive mesenchymal stromal cells for use in clinical trials.
        Cytotherapy. 2019; 21: 546-560
        • Thavorn K.
        • van Katwyk S.
        • Krahn M.
        • Mei S.H.J.
        • Stewart D.J.
        • Fergusson D.
        • et al.
        Value of mesenchymal stem cell therapy for patients with septic shock: an early health economic evaluation.
        Int J Technol Assess Health Care. 2020; 36: 525-532
        • van Es M.A.
        • Diekstra F.P.
        • Veldink J.H.
        • Baas F.
        • Bourque P.R.
        • Schelhaas H.J.
        • et al.
        A case of ALS-FTD in a large FALS pedigree with a K17I ANG mutation.
        Neurology. 2009; 72: 287-288
        • Vander Beken S.
        • de Vries J.C.
        • Meier-Schiesser B.
        • Meyer P.
        • Jiang D.
        • Sindrilaru A.
        • et al.
        Newly Defined ATP-Binding Cassette Subfamily B Member 5 Positive Dermal Mesenchymal Stem Cells Promote Healing of Chronic Iron-Overload Wounds via Secretion of Interleukin-1 Receptor Antagonist.
        Stem cells (Dayton, Ohio). 2019; 37: 1057-1074
        • Wang H.
        • Fan D.
        • Zhang Y.
        Angiogenin gene polymorphism: A risk factor for diabetic peripheral neuropathy in the northern Chinese Han population.
        Neural Regen Res. 2013; 8: 3434-3440
        • Wang X.
        • Li W.
        • Williams M.
        • Terada N.
        • Alessi D.R.
        • Proud C.G.
        Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase.
        EMBO J. 2001; 20: 4370-4379
        • Xiao Y.
        • Reis L.A.
        • Feric N.
        • Knee E.J.
        • Gu J.
        • Cao S.
        • et al.
        Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization.
        Proceedings of the National Academy of Sciences of the United States of America. 2016; 113 (E5792-e801)