Cell-based vascularization strategies for skin tissue engineering.

Providing a blood-vascular network to promote survival and integration of cells in thick dermal substitutes for application in full-thickness wounds is essential for the successful outcome of skin tissue engineering. Nevertheless, promoting vascularization also represents a critical bottleneck in today's skin tissue engineering practice. Several cell types have been considered and tested, mostly in preclinical studies, to increase vascularization. When the clinical situation allows delayed reconstruction of the defect, an autologous approach is preferable, whereas in acute cases allogeneic therapy is needed. In both cases, the cells should be harvested with minimal donor-site morbidity and should be available in large amounts and safe in terms of tumor formation and transmission of animal diseases. Here, we outline the different mechanisms of cell-based vascularization and subsequently elaborate in more detail on the candidate cell types and their pros and cons in terms of clinical application and regulation of the wound healing process.

[1]  Lucie Germain,et al.  In vitro reconstruction of a human capillary‐like network in a tissue‐engineered skin equivalent , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[2]  J. Pober,et al.  Engraftment of a vascularized human skin equivalent , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  Tomoyuki Nishikawa,et al.  Novel Autologous Cell Therapy in Ischemic Limb Disease Through Growth Factor Secretion by Cultured Adipose Tissue–Derived Stromal Cells , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[4]  K. Nakao,et al.  Induction and Isolation of Vascular Cells From Human Induced Pluripotent Stem Cells—Brief Report , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[5]  A. Luttun,et al.  In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells , 2006 .

[6]  Benoit Hendrickx,et al.  Integration of Blood Outgrowth Endothelial Cells in Dermal Fibroblast Sheets Promotes Full Thickness Wound Healing , 2010, Stem cells.

[7]  G. Gurtner,et al.  Skin Graft Vascularization Involves Precisely Regulated Regression and Replacement of Endothelial Cells through Both Angiogenesis and Vasculogenesis , 2006, Plastic and reconstructive surgery.

[8]  H. Lorenz,et al.  Multilineage cells from human adipose tissue: implications for cell-based therapies. , 2001, Tissue engineering.

[9]  K. Bensch,et al.  Isolation and growth of endothelial cells from the microvessels of the newborn human foreskin in cell culture. , 1980, The Journal of investigative dermatology.

[10]  J. Vojtaššák,et al.  Autologous biograft and mesenchymal stem cells in treatment of the diabetic foot. , 2006, Neuro endocrinology letters.

[11]  J. Cigudosa,et al.  Spontaneous human adult stem cell transformation. , 2005, Cancer research.

[12]  V. V. van Hinsbergh,et al.  Blood outgrowth endothelial cells from cord blood and peripheral blood: angiogenesis‐related characteristics in vitro , 2009, Journal of thrombosis and haemostasis : JTH.

[13]  Anthony Atala,et al.  Functional small-diameter neovessels created using endothelial progenitor cells expanded ex vivo , 2001, Nature Medicine.

[14]  D. García-Olmo,et al.  Expanded Adipose-Derived Stem Cells for the Treatment of Complex Perianal Fistula: a Phase II Clinical Trial , 2009, Diseases of the colon and rectum.

[15]  K. Liechty,et al.  Multipotent adult progenitor cells: their role in wound healing and the treatment of dermal wounds. , 2008, Cytotherapy.

[16]  T. Pohlemann,et al.  A new in vitro wound model based on the co‐culture of human dermal microvascular endothelial cells and human dermal fibroblasts , 2007, Biology of the cell.

[17]  B. Lévy,et al.  Plasticity of Human Adipose Lineage Cells Toward Endothelial Cells: Physiological and Therapeutic Perspectives , 2004, Circulation.

[18]  David J Mooney,et al.  Engineering and Characterization of Functional Human Microvessels in Immunodeficient Mice , 2001, Laboratory Investigation.

[19]  Dai Fukumura,et al.  Differential in vivo potential of endothelial progenitor cells from human umbilical cord blood and adult peripheral blood to form functional long-lasting vessels. , 2008, Blood.

[20]  A. Reinisch,et al.  Isolation and animal serum free expansion of human umbilical cord derived mesenchymal stromal cells (MSCs) and endothelial colony forming progenitor cells (ECFCs). , 2009, Journal of visualized experiments : JoVE.

[21]  M. Yoder,et al.  Human CD34+AC133+VEGFR-2+ cells are not endothelial progenitor cells but distinct, primitive hematopoietic progenitors. , 2007, Experimental hematology.

[22]  R. Galiano,et al.  Differential effects of oxygen on human dermal fibroblasts: acute versus chronic hypoxia , 1996, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[23]  J. Prchal,et al.  Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. , 2007, Blood.

[24]  S. Spiekstra,et al.  Wound‐healing factors secreted by epidermal keratinocytes and dermal fibroblasts in skin substitutes , 2007, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[25]  K. Pollok,et al.  Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. , 2004, Blood.

[26]  Shayn M Peirce,et al.  IFATS Collection: The Role of Human Adipose‐Derived Stromal Cells in Inflammatory Microvascular Remodeling and Evidence of a Perivascular Phenotype , 2008, Stem cells.

[27]  H Green,et al.  Growth of cultured human epidermal cells into multiple epithelia suitable for grafting. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Joyce Bischoff,et al.  Tissue-engineered microvessels on three-dimensional biodegradable scaffolds using human endothelial progenitor cells. , 2004, American journal of physiology. Heart and circulatory physiology.

[29]  K. Burg,et al.  Comparative study of seeding methods for three-dimensional polymeric scaffolds , 2000, Journal of biomedical materials research.

[30]  O Damour,et al.  A tissue‐engineered endothelialized dermis to study the modulation of angiogenic and angiostatic molecules on capillary‐like tube formation in vitro , 2003, The British journal of dermatology.

[31]  David J. Mooney,et al.  DNA delivery from polymer matrices for tissue engineering , 1999, Nature Biotechnology.

[32]  Q. Han,et al.  Human adipose tissue-derived stem cells differentiate into endothelial cells in vitro and improve postnatal neovascularization in vivo. , 2005, Biochemical and biophysical research communications.

[33]  Nicola J Brown,et al.  Development of a reconstructed human skin model for angiogenesis , 2003, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[34]  Origin of endothelial progenitors in human postnatal bone marrow , 2002 .

[35]  Joyce Bischoff,et al.  In vivo vasculogenic potential of human blood-derived endothelial progenitor cells. , 2007, Blood.

[36]  Jin‐Ho Choi,et al.  Transplantation of Endothelial Progenitor Cells Accelerates Dermal Wound Healing with Increased Recruitment of Monocytes/Macrophages and Neovascularization , 2005, Stem cells.

[37]  Andrea T. Badillo,et al.  Treatment of diabetic wounds with fetal murine mesenchymal stromal cells enhances wound closure , 2007, Cell and Tissue Research.

[38]  J. Schechner,et al.  In Vivo Perfusion of Human Skin Substitutes With Microvessels Formed by Adult Circulating Endothelial Progenitor Cells , 2008, Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.].

[39]  Christie M. Orschell,et al.  Peripheral Blood “Endothelial Progenitor Cells” Are Derived From Monocyte/Macrophages and Secrete Angiogenic Growth Factors , 2003, Circulation.

[40]  Hideki Uosaki,et al.  Directed and Systematic Differentiation of Cardiovascular Cells From Mouse Induced Pluripotent Stem Cells , 2008, Circulation.

[41]  Min Zhu,et al.  Comparison of Multi-Lineage Cells from Human Adipose Tissue and Bone Marrow , 2003, Cells Tissues Organs.

[42]  Thomas A. Mustoe, MD, FACS,et al.  Hypoxia increases human keratinocyte motility on connective tissue. , 1997, The Journal of clinical investigation.

[43]  N. Pallua,et al.  Human Bone Marrow Mesenchymal Stem Cells Seeded on Modified Collagen Improved Dermal Regeneration In Vivo , 2006, Cell transplantation.

[44]  Lei Yuan,et al.  Engineering Robust and Functional Vascular Networks In Vivo With Human Adult and Cord Blood–Derived Progenitor Cells , 2008, Circulation research.

[45]  J. Pober,et al.  Cytoprotection of Human Umbilical Vein Endothelial Cells Against Apoptosis and CTL-Mediated Lysis Provided by Caspase-Resistant Bcl-2 Without Alterations in Growth or Activation Responses1 , 2000, The Journal of Immunology.

[46]  H. Shimizu,et al.  Mesenchymal Stem Cells Are Recruited into Wounded Skin and Contribute to Wound Repair by Transdifferentiation into Multiple Skin Cell Type1 , 2008, The Journal of Immunology.

[47]  D. García-Olmo,et al.  A Phase I Clinical Trial of the Treatment of Crohn’s Fistula by Adipose Mesenchymal Stem Cell Transplantation , 2005, Diseases of the colon and rectum.

[48]  W. Fiers,et al.  Lymphocytes recognize human vascular endothelial and dermal fibroblast Ia antigens induced by recombinant immune interferon , 1983, Nature.

[49]  K. Nakao,et al.  Augmentation of Neovascularizaiton in Hindlimb Ischemia by Combined Transplantation of Human Embryonic Stem Cells-Derived Endothelial and Mural Cells , 2008, PloS one.

[50]  J. Thomson,et al.  Hematopoietic and Endothelial Differentiation of Human Induced Pluripotent Stem Cells , 2009, Stem cells.

[51]  A. Perets,et al.  Enhancing the vascularization of three-dimensional porous alginate scaffolds by incorporating controlled release basic fibroblast growth factor microspheres. , 2003, Journal of biomedical materials research. Part A.

[52]  Kevin McIntosh,et al.  Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. , 2002, Experimental hematology.

[53]  Yilin Cao,et al.  Tissue engineering of blood vessels with endothelial cells differentiated from mouse embryonic stem cells , 2003, Cell Research.

[54]  T. Yoshikawa,et al.  Wound Therapy by Marrow Mesenchymal Cell Transplantation , 2008, Plastic and reconstructive surgery.

[55]  Catherine M. Verfaillie,et al.  Pluripotency of mesenchymal stem cells derived from adult marrow , 2002, Nature.

[56]  Rui L Reis,et al.  Contribution of outgrowth endothelial cells from human peripheral blood on in vivo vascularization of bone tissue engineered constructs based on starch polycaprolactone scaffolds. , 2009, Biomaterials.

[57]  A. Condurache,et al.  VEGF165 and bFGF protein-based therapy in a slow release system to improve angiogenesis in a bioartificial dermal substitute in vitro and in vivo , 2007, Langenbeck's Archives of Surgery.

[58]  G Tellides,et al.  In vivo formation of complex microvessels lined by human endothelial cells in an immunodeficient mouse. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[59]  O. Lee,et al.  Isolation of multipotent mesenchymal stem cells from umbilical cord blood. , 2004, Blood.

[60]  Christof von Kalle,et al.  A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. , 2003, The New England journal of medicine.

[61]  V. Falanga,et al.  Treatment of chronic wounds with bone marrow-derived cells. , 2003, Archives of dermatology.

[62]  I. Marzi,et al.  Systemic transplantation of progenitor cells accelerates wound epithelialization and neovascularization in the hairless mouse ear wound model. , 2011, The Journal of surgical research.

[63]  M. Detmar,et al.  A simple immunomagnetic protocol for the selective isolation and long-term culture of human dermal microvascular endothelial cells. , 1998, Experimental cell research.

[64]  A. Caplan,et al.  A Self-Assembled Fibroblast-Endothelial Cell Co-Culture System That Supports in vitro Vasculogenesis by both Human Umbilical Vein Endothelial Cells and Human Dermal Microvascular Endothelial Cells , 2007, Cells Tissues Organs.

[65]  S. Han,et al.  In vitro endothelial potential of human UC blood-derived mesenchymal stem cells. , 2006, Cytotherapy.

[66]  Lucie Germain,et al.  Inosculation of Tissue‐Engineered Capillaries with the Host's Vasculature in a Reconstructed Skin Transplanted on Mice , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[67]  M. Yoder,et al.  Unresolved questions, changing definitions, and novel paradigms for defining endothelial progenitor cells. , 2005, Blood.

[68]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[69]  Hoon Han,et al.  Successful Stem Cell Therapy Using Umbilical Cord Blood‐Derived Multipotent Stem Cells for Buerger's Disease and Ischemic Limb Disease Animal Model , 2006, Stem cells.

[70]  S. Gerson,et al.  Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH) , 2002, Bone Marrow Transplantation.

[71]  Karl Kashofer,et al.  Human platelet lysate can replace fetal bovine serum for clinical‐scale expansion of functional mesenchymal stromal cells , 2007, Transfusion.

[72]  M. Spector,et al.  In vitro response of the bone marrow-derived mesenchymal stem cells seeded in a type-I collagen-glycosaminoglycan scaffold for skin wound repair under the mechanical loading condition. , 2009, Molecular & cellular biomechanics : MCB.

[73]  J. McGrath,et al.  The role of fibroblasts in tissue engineering and regeneration , 2007, The British journal of dermatology.

[74]  M. Burnett,et al.  Marrow-Derived Stromal Cells Express Genes Encoding a Broad Spectrum of Arteriogenic Cytokines and Promote In Vitro and In Vivo Arteriogenesis Through Paracrine Mechanisms , 2004, Circulation research.

[75]  Y. Bae,et al.  Human Adipose Tissue-Derived Mesenchymal Stem Cells Improve Postnatal Neovascularization in a Mouse Model of Hindlimb Ischemia , 2006, Cellular Physiology and Biochemistry.

[76]  A. Luttun,et al.  Multipotent adult progenitor cells sustain function of ischemic limbs in mice. , 2008, The Journal of clinical investigation.

[77]  J. Koponen,et al.  Umbilical Cord Blood-derived Progenitor Cells Enhance Muscle Regeneration in Mouse Hindlimb Ischemia Model. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[78]  Sha Huang,et al.  Tissue-engineered skin containing mesenchymal stem cells improves burn wounds. , 2008, Artificial organs.

[79]  P. Hematti,et al.  Mesenchymal Stem Cell Therapy for Nonhealing Cutaneous Wounds , 2010, Plastic and reconstructive surgery.

[80]  R. de Caterina,et al.  Adipose tissue-derived stem cells: characterization and potential for cardiovascular repair. , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[81]  Xiaobing Fu,et al.  Mesenchymal stem cells and skin wound repair and regeneration: possibilities and questions , 2009, Cell and Tissue Research.

[82]  T. Suganuma,et al.  Beyond vasodilation: the antioxidant effect of adrenomedullin in Dahl salt-sensitive rat aorta. , 2005, Biochemical and biophysical research communications.

[83]  A. Ibatici,et al.  Clinical scale ex vivo expansion of cord blood-derived outgrowth endothelial progenitor cells is associated with high incidence of karyotype aberrations. , 2008, Experimental hematology.

[84]  A. Wobus,et al.  Induced human pluripotent stem cells: promises and open questions , 2009, Biological chemistry.

[85]  H. Mikkers,et al.  Tumors Originating from Induced Pluripotent Stem Cells and Methods for Their Prevention , 2009, Annals of the New York Academy of Sciences.

[86]  D. Heimbach,et al.  Artificial Dermis for Major Burns: A Multi‐Center Randomized Clinical Trial , 1988, Annals of surgery.

[87]  Alexander M Seifalian,et al.  The roles of tissue engineering and vascularisation in the development of micro-vascular networks: a review. , 2005, Biomaterials.

[88]  R Busse,et al.  Improvement of Postnatal Neovascularization by Human Adipose Tissue–Derived Stem Cells , 2004, Circulation.

[89]  Paul G Scott,et al.  Mesenchymal Stem Cells Enhance Wound Healing Through Differentiation and Angiogenesis , 2007, Stem cells.

[90]  R. Bareille,et al.  Human progenitor‐derived endothelial cells vs. venous endothelial cells for vascular tissue engineering: an in vitro study , 2010, Journal of tissue engineering and regenerative medicine.

[91]  Baojin Fu,et al.  Accumulated Chromosomal Instability in Murine Bone Marrow Mesenchymal Stem Cells Leads to Malignant Transformation , 2006, Stem cells.

[92]  W. Arap,et al.  A Population of Multipotent CD34-Positive Adipose Stromal Cells Share Pericyte and Mesenchymal Surface Markers, Reside in a Periendothelial Location, and Stabilize Endothelial Networks , 2008, Circulation research.

[93]  Hyun-Jai Cho,et al.  Cytokines and Matrix Metalloproteinases Progenitor Cells and Late Outgrowth Endothelial Cells: the Role of Angiogenic Synergistic Neovascularization by Mixed Transplantation of Early Endothelial Synergistic Neovascularization by Mixed Transplantation of Early Endothelial Progenitor Cells and Late Ou , 2022 .

[94]  A. Luttun,et al.  Will the real EPC please stand up , 2007 .

[95]  C. Verfaillie,et al.  Mouse MAPC-mediated immunomodulation: Cell-line dependent variation. , 2010, Experimental Hematology.

[96]  V. Falanga,et al.  Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. , 2007, Tissue engineering.

[97]  Junbiao Chang,et al.  Placental mesenchymal and cord blood stem cell therapy for dilated cardiomyopathy. , 2008, Reproductive biomedicine online.

[98]  C. Jiao,et al.  Differential Healing Activities of CD34+ and CD14+ Endothelial Cell Progenitors , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[99]  J. Mao,et al.  Synergistic Actions of Hematopoietic and Mesenchymal Stem/Progenitor Cells in Vascularizing Bioengineered Tissues , 2008, PloS one.

[100]  V. Morhenn,et al.  Interleukin-2 stimulates resting human T lymphocytes' response to allogeneic, gamma interferon-treated keratinocytes. , 1987, The Journal of investigative dermatology.

[101]  J. Tolar,et al.  Multipotent adult progenitor cells can suppress graft-versus-host disease via prostaglandin E2 synthesis and only if localized to sites of allopriming. , 2009, Blood.

[102]  H. Hauner,et al.  Tissue engineering of white adipose tissue using hyaluronic acid-based scaffolds. I: in vitro differentiation of human adipocyte precursor cells on scaffolds. , 2003, Biomaterials.

[103]  R. Hebbel,et al.  A novel technique for culture of human dermal microvascular endothelial cells under either serum-free or serum-supplemented conditions: isolation by panning and stimulation with vascular endothelial growth factor. , 1997, Experimental cell research.

[104]  Hermann Eichler,et al.  Comparative Analysis of Mesenchymal Stem Cells from Bone Marrow, Umbilical Cord Blood, or Adipose Tissue , 2006, Stem cells.

[105]  D. Celermajer,et al.  Strikingly different angiogenic properties of endothelial progenitor cell subpopulations: insights from a novel human angiogenesis assay. , 2008, Journal of the American College of Cardiology.

[106]  Chandan K Sen,et al.  Wound healing essentials: Let there be oxygen , 2009, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[107]  R. Hebbel,et al.  Origins of circulating endothelial cells and endothelial outgrowth from blood. , 2000, The Journal of clinical investigation.

[108]  A. Mathur,et al.  IFATS Collection: Human Adipose‐Derived Stem Cells Seeded on a Silk Fibroin‐Chitosan Scaffold Enhance Wound Repair in a Murine Soft Tissue Injury Model , 2009, Stem cells.

[109]  Z. Upton,et al.  Serum-free primary human fibroblast and keratinocyte coculture. , 2010, Tissue engineering. Part A.

[110]  Y. Suárez,et al.  Vascularization and engraftment of a human skin substitute using circulating progenitor cell‐derived endothelial cells , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[111]  A. Luttun,et al.  Emerging hurdles in stem cell therapy for peripheral vascular disease , 2008, Journal of Molecular Medicine.

[112]  J. Park,et al.  Wound healing effect of adipose-derived stem cells: a critical role of secretory factors on human dermal fibroblasts. , 2007, Journal of dermatological science.

[113]  Sheila MacNeil,et al.  Progress and opportunities for tissue-engineered skin , 2007, Nature.

[114]  D. Kaufman,et al.  Multilineage Differentiation from Human Embryonic Stem Cell Lines , 2001, Stem cells.

[115]  Liwen Chen,et al.  Paracrine Factors of Mesenchymal Stem Cells Recruit Macrophages and Endothelial Lineage Cells and Enhance Wound Healing , 2008, PloS one.

[116]  S. Dickens,et al.  Regulable vascular endothelial growth factor165 overexpression by ex vivo expanded keratinocyte cultures promotes matrix formation, angiogenesis, and healing in porcine full-thickness wounds. , 2008, Tissue engineering. Part A.

[117]  A. Luttun,et al.  Comparative transcriptome analysis of embryonic and adult stem cells with extended and limited differentiation capacity , 2007, Genome Biology.

[118]  F. Locatelli,et al.  Mesenchymal Stromal Cells , 2009, Annals of the New York Academy of Sciences.

[119]  Jun Yamashita,et al.  Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors , 2000, Nature.

[120]  K. Hirschi,et al.  Assessing identity, phenotype, and fate of endothelial progenitor cells. , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[121]  D. Supp,et al.  Human dermal microvascular endothelial cells form vascular analogs in cultured skin substitutes after grafting to athymic mice , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[122]  R. Cortivo,et al.  In vitro reconstruction of human dermal equivalent enriched with endothelial cells. , 2003, Biomaterials.

[123]  E. Jaffe,et al.  Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. , 1973, The Journal of clinical investigation.

[124]  M. Arévalo,et al.  Reduced angiogenic responses in adult Endoglin heterozygous mice. , 2006, Cardiovascular research.

[125]  Takayuki Asahara,et al.  Isolation of Putative Progenitor Endothelial Cells for Angiogenesis , 1997, Science.

[126]  R. Stewart,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.