title: A step towards clinical application of acellular matrix: A clue from macrophage polarization.
abstract: The outcome of tissue engineered organ transplants depends on the capacity of the biomaterial to promote a pro-healing response once implanted in vivo. Multiple studies, including ours, have demonstrated the possibility of using the extracellular matrix (ECM) of animal organs as platform for tissue engineering and more recently, discarded human organs have also been proposed as scaffold source. In contrast to artificial biomaterials, natural ECM has the advantage of undergoing continuous remodeling which allows adaptation to diverse conditions. It is known that natural matrices present diverse immune properties when compared to artificial biomaterials. However, how these properties compare between diseased and healthy ECM and artificial scaffolds has not yet been defined. To answer this question, we used decellularized renal ECM derived from WT mice and from mice affected by Alport Syndrome at different time-points of disease progression as a model of renal failure with extensive fibrosis. We characterized the morphology and composition of these ECMs and compared their in vitro effects on macrophage activation with that of synthetic scaffolds commonly used in the clinic (collagen type I and poly-L-(lactic) acid, PLLA). We showed that ECM derived from Alport kidneys differed in fibrous protein deposition and cytokine content when compared to ECM derived from WT kidneys. Yet, both WT and Alport renal ECM induced macrophage differentiation mainly towards a reparative (M2) phenotype, while artificial biomaterials towards an inflammatory (M1) phenotype. Anti-inflammatory properties of natural ECMs were lost when homogenized, hence three-dimensional structure of ECM seems crucial for generating an anti-inflammatory response. Together, these data support the notion that natural ECM, even if derived from diseased kidneys promote a M2 protolerogenic macrophage polarization, thus providing novel insights on the applicability of ECM obtained from discarded organs as ideal scaffold for tissue engineering.
authors: GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics, Saban Research Institute, Children's Hospital Los Angeles, Department of Urology, University of Southern California, Los Angeles, CA 90027, USA.
authors: Astgik
authors: A
authors: Petrosyan
authors: GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics, Saban Research Institute, Children's Hospital Los Angeles, Department of Urology, University of Southern California, Los Angeles, CA 90027, USA.
authors: Stefano
authors: S
authors: Da Sacco
authors: GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics, Saban Research Institute, Children's Hospital Los Angeles, Department of Urology, University of Southern California, Los Angeles, CA 90027, USA.
authors: Nikita
authors: N
authors: Tripuraneni
authors: Radboud Institute for Molecular Life Sciences, Department of Physiology, 6525 GA Nijmegen, The Netherlands.
authors: Ursula
authors: U
authors: Kreuser
authors: GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics, Saban Research Institute, Children's Hospital Los Angeles, Department of Urology, University of Southern California, Los Angeles, CA 90027, USA.
authors: Maria
authors: M
authors: Lavarreda-Pearce
authors: Department of General Surgery, Section of Transplantation, Wake Forest School of Medicine, Winston Salem, NC 27157, USA.
authors: Riccardo
authors: R
authors: Tamburrini
authors: GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics, Saban Research Institute, Children's Hospital Los Angeles, Department of Urology, University of Southern California, Los Angeles, CA 90027, USA.
authors: Roger E
authors: RE
authors: De Filippo
authors: Department of General Surgery, Section of Transplantation, Wake Forest School of Medicine, Winston Salem, NC 27157, USA.
authors: Giuseppe
authors: G
authors: Orlando
authors: Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Annenberg Building, New York, NY 10029, USA.
authors: Paolo
authors: P
authors: Cravedi
authors: GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics, Saban Research Institute, Children's Hospital Los Angeles, Department of Urology, University of Southern California, Los Angeles, CA 90027, USA. Electronic address: lperin@chla.usc.edu.
authors: Laura
authors: L
authors: Perin
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology; D024042:Collagen Type I / Q000737:chemistry / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000737:chemistry* / Q000276:immunology / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D007668:Kidney / Q000737:chemistry* / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000145:classification / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009394:Nephritis, Hereditary / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011091:Polyesters / Q000737:chemistry / Q000494:pharmacology; D061251:Primary Cell Culture; D023822:Tissue Engineering / Q000379:methods; D054457:Tissue Scaffolds
chemical_list: D000893:Anti-Inflammatory Agents; D024042:Collagen Type I; D016207:Cytokines; D011091:Polyesters; C033616:poly(lactide)
keywords: Cell–matrix interactions; Macrophages; Renal extracellular matrix scaffolds (ECM)