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Modulation of monocytes, macrophages and pericytes by the colony stimulating factor genes to treat murine limb ischemia

Grant number: 15/20206-8
Support Opportunities:Research Projects - Thematic Grants
Duration: December 01, 2015 - May 31, 2023
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Sang Won Han
Grantee:Sang Won Han
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated researchers: Eduardo Alexandre Barros e Silva ; Elizabeth Suchi Chen ; José Carlos Costa Baptista-Silva ; Leonardo Pinto de Carvalho ; Lindolfo da Silva Meirelles ; Lucimara Gaziola de la Torre ; Marcos Augusto Bizeto ; Marilia de Arruda Cardoso Smith ; Vívian Yochiko Samoto
Associated grant(s):18/06635-1 - Development of effective biomaterial-based systems for the efficient and safe delivery of iPSC-derived macrophages into the skeletal muscle to treat limb ischemia, AP.R SPRINT
Associated scholarship(s):20/02313-0 - Microfluidic and 3D bioprinting routes for the development of macrophage encapsulation systems based on hybrid gellan and fibrin hydrogels, BP.PD
20/06913-1 - Development of chitosomes' nanoparticles for modulation of inflammation and angiogenesis by dual delivery: an approach to gene therapy for limb ischemia, BP.DR
19/13518-4 - Core-shell non-viral vectors synthesis for gene dual delivery, BP.IC
+ associated scholarships 18/18523-3 - Polymeric microparticle synthesis via droplet microfluidics for sustained release of non-viral vectors applied to gene therapy, BP.DD
18/09203-5 - Genetic engineering of macrophages to acquire Phd2 +/- phenotype from induced pluripotent stem cells and its use for treatment of Limb Ischemia, BP.PD
17/20341-8 - Polymeric microparticle synthesis via droplet microfluidics for sustained release of non-viral vectors applied to gene therapy, BP.MS
17/17588-1 - Forced expression effect of GM-CSF and M-CSF genes in ischemic skeletal muscle, BP.PD
16/04229-0 - Evaluation of regenerative and reparative effect of IL-4 in ischemic muscle through expansion of type m2 resident macrophages, BP.MS
16/09547-0 - Gene therapy with CX3CL1 for murine limb ischemia, BP.IC - associated scholarships


Peripheral arterial disease affects millions of people every year and compromises the quality of life and shortens the life expectancy of these patients. The non-healing ulcer and strong chronic pain are the main symptoms of this disease in advanced stage that occurs due to tissue hypoperfusion and can lead to amputation of the affected limb and death. In the ischemic limb a constant inflammation occurs due to hypoperfusion and cell death, and monocytes and macrophages are mobilized to remove necrotic cells and to produce growth factors to promote vessel formation and remodeling, and regeneration and tissue repair. Recently, several subpopulations of monocytes and macrophages were discovered with several biological and paradoxical activities that may favor or disfavor the injured ischemic muscle. The proliferation and differentiation of these cells are dependent on the colony stimulating factors (CSFs), but subtypes of monocytes and macrophages recruited by each CSFs and the influence of these macrophages upon pericytes in the ischemic limb are unknown. The importance of understanding the role of CSFs in gene and cell therapies for ischemic diseases comes from our previous experience, where the administration of GM-CSF gene in vivo or ex vivo by means of mesenchymal stem cells in the mouse ischemic limbs led to almost complete recovery of mass and strength of muscles in 30 days. The main focus of this project is to study the quality of populations of monocytes and macrophages recruited by different CSFs in the ischemic skeletal muscles, and to assess whether the restriction of the M1 macrophage population or recruitment of M2 population is beneficial, and to verify if the tissue macrophage profiles can be changed by the local microenvironment. Influence of macrophages upon pericytes under ischemic and normoxica conditions will be investigated. Results of this study will show new gene interference ways to promote vessel formation and remodeling to repair and to regenerate ischemic tissue more efficiently with less fibrosis. (AU)

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Scientific publications (26)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CINEL, VICTOR DAL POSOLO; TAKETA, THIAGO BEZERRA; DE CARVALHO, BRUNA GREGATTI; DE LA TORRE, LUCIMARA GAZIOLA; DE MELLO, LUCAS RODRIGUES; DA SILVA, EMERSON RODRIGO; HAN, SANG WON. Microfluidic encapsulation of nanoparticles in alginate microgels gelled via competitive ligand exchange crosslinking. Biopolymers, v. 112, n. 7, . (18/19537-8, 18/18523-3, 19/19719-1, 18/06635-1, 15/20206-8)
MEIRELLES, LINDOLFO DA SILVA; MARSON, RENAN FAVA; GONZALEZ SOLARI, MARIA INES; NARDI, NANCE BEYER. Are Liver Pericytes Just Precursors of Myofibroblasts in Hepatic Diseases? Insights from the Crosstalk between Perivascular and Inflammatory Cells in Liver Injury and Repair. CELLS, v. 9, n. 1, . (15/20206-8)
STILHANO, ROBERTA SESSA; ANDRADE DENAPOLI, PRISCILA MARTINS; GALLO, CAMILA CONGENTINO; SAMOTO, VIVIAN YOCHIKO; MCNEILL INGHAM, SHEILA JEAN; ABDALLA, RENE JORGE; KOH, TIMOTHY JON; HAN, SANG WON. Regenerative effect of platelet-rich plasma in the murine ischemic limbs. Life Sciences, v. 284, . (15/20206-8, 11/09687-3)
CARVALHO, BRUNA G.; GARCIA, BIANCA B. M.; MALFATTI-GASPERINI, ANTONIO A.; HAN, SANG W.; DE LA TORRE, LUCIMARA G.. Hybrid polymer/lipid vesicle synthesis: Association between cationic liposomes and lipoplexes with chondroitin sulfate. COLLOIDS AND SURFACES B-BIOINTERFACES, v. 210, . (15/20206-8, 18/18523-3, 18/19537-8)
DE CARVALHO, BRUNA GREGATTI; TAKETA, THIAGO BEZERRA; MORENO GARCIA, BIANCA BONETTO; HAN, SANG WON; DE LA TORRE, LUCIMARA GAZIOLA. Hybrid microgels produced via droplet microfluidics for sustainable delivery of hydrophobic and hydrophilic model nanocarriers. Materials Science & Engineering C-Materials for Biological Applications, v. 118, . (18/19537-8, 15/20206-8, 18/18523-3)
MORENO GARCIA, BIANCA BONETTO; DOUKA, STEFANIA; MERTINS, OMAR; MASTROBATTISTA, ENRICO; HAN, SANG WON. Optimization of Chitosan-Lipid Hybrid Nanoparticles for mRNA Delivery. MOLECULAR THERAPY, v. 31, n. 4, p. 2-pg., . (22/04361-7, 15/20206-8, 20/06913-1)
GALLO, CAMILA CONGENTINO; HONDA, TAMISA SEEKO BANDEIRA; ALVES, PATRICIA TERRA; HAN, SANG WON. Macrophages mobilized by the overexpression of the macrophage-colony stimulating factor promote efficient recovery of the ischemic muscle functionality. Life Sciences, v. 317, p. 11-pg., . (15/20206-8)
STILHANO, ROBERTA SESSA; SAMOTO, VIVIAN YOCHIKO; SILVA, LEONARDO MARTINS; PEREIRA, GUSTAVO JOSE; ERUSTES, ADOLFO GARCIA; SMAILI, SORAYA SOUBHI; HAN, SANG WON. Reduction in skeletal muscle fibrosis of spontaneously hypertensive rats after laceration by microRNA targeting angiotensin II receptor. PLoS One, v. 12, n. 10, . (12/00753-6, 15/20206-8)
MADRIGAL, JUSTIN L.; STILHANO, ROBERTA S.; SILTANEN, CHRISTIAN; TANAKA, KIMBERLY; REZVANI, SABAH N.; MORGAN, RYAN P.; REVZIN, ALEXANDER; HAN, SANG W.; SILVA, EDUARDO A.. Microfluidic generation of alginate microgels for the controlled delivery of lentivectors. JOURNAL OF MATERIALS CHEMISTRY B, v. 4, n. 43, p. 6989-6999, . (12/00753-6, 15/20206-8)
MERTINS, OMAR; LOBO, SONJA ELLEN; MATHEWS, PATRICK D.; HAN, SANG WON. Interaction of pDNA with reverse phase chitosome. COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS, v. 543, p. 76-82, . (16/13368-4, 15/20206-8, 15/23948-5)
STILHANO, ROBERTA S.; MADRIGAL, JUSTIN L.; WONG, KEVIN; WILLIAMS, PRISCILLA A.; MARTIN, PRISCILA K. M.; YAMAGUCHI, FABIO S. M.; SAMOTO, VIVIAN Y.; HAN, SANG W.; SILVA, EDUARDO A.. Injectable alginate hydrogel for enhanced spatiotemporal control of lentivector delivery in murine skeletal muscle. JOURNAL OF CONTROLLED RELEASE, v. 237, p. 42-49, . (15/20206-8)
RODRIGUES COSTA, ANA LETICIA; WILLERTH, STEPHANIE M.; DE LA TORRE, LUCIMARA GAZIOLA; HAN, SANG WON. Trends in hydrogel-based encapsulation technologies for advanced cell therapies applied to limb ischemia. MATERIALS TODAY BIO, v. 13, p. 19-pg., . (18/06635-1, 18/19537-8, 20/02313-0, 15/20206-8)
DE MELLO, LUCAS RODRIGUES; HAMLEY, IAN WILLIAM; CASTELLETTO, VALERIA; MORENO GARCI, BIANCA BONETTO; HAN, SANG WON; PINTO DE OLIVEIRA, CRISTIANO LUIS; DA SILV, EMERSON RODRIGO A. Nanoscopic Structure of Complexes Formed between DNA and the Cell-Penetrating Peptide Penetratin. Journal of Physical Chemistry B, v. 123, n. 42, p. 8861-8871, . (15/20206-8, 16/24409-3)
GARCIA, BIANCA B. M.; MERTINS, OMAR; DA SILVA, EMERSON R.; MATHEWS, PATRICK D.; HAN, SANG W.. Arginine-modified chitosan complexed with liposome systems for plasmid DNA delivery. COLLOIDS AND SURFACES B-BIOINTERFACES, v. 193, . (16/13368-4, 15/23948-5, 15/20206-8)
MARTINS, GRAZIELI OLINDA; PETRONIO, MAICON SEGALLA; FURUYAMA LIMA, ALINE MARGARETE; MARTINEZ JUNIOR, ANDRE MIGUEL; DE OLIVEIRA TIERA, VERA APARECIDA; CALMON, MARILIA DE FREITAS; LEITE VILAMAIOR, PATRICIA SIMONE; HAN, SANG WON; TIERA, MARCIO JOSE. Amphipathic chitosans improve the physicochemical properties of siRNA-chitosan nanoparticles at physiological conditions. Carbohydrate Polymers, v. 216, p. 332-342, . (17/10331-5, 12/24259-0, 15/05148-1, 15/20206-8)
SANG WON HAN; CARLOS ALBERTO VERGANI JUNIOR; PAULO EDUARDO OCKE REIS. Terapia gênica de isquemia de membro é uma realidade?. Jornal Vascular Brasileiro, v. 19, . (15/20206-8)
CARVALHO, BRUNA G.; VIT, FRANCIELE F.; CARVALHO, HERNANDES F.; HAN, SANG W.; DE LA TORRE, LUCIMARA G.. Layer-by-Layer Biomimetic Microgels for 3D Cell Culture and Nonviral Gene Delivery. Biomacromolecules, . (18/18523-3, 15/20206-8, 18/19537-8, 17/20341-8)
CARVALHO, BRUNA G.; CECCATO, BRUNO T.; MICHELON, MARIANO; HAN, SANG W.; DE LA TORRE, LUCIMARA G.. dvanced Microfluidic Technologies for Lipid Nano-Microsystems from Synthesis to Biological Applicatio. HARMACEUTIC, v. 14, n. 1, . (15/20206-8, 18/18523-3, 18/19537-8)
MARSON, RENAN FAVA; REGNER, ANDREA PEREIRA; MEIRELLES, LINDOLFO DA SILVA. Mesenchymal "stem" cells, or facilitators for the development of regenerative macrophages? Pericytes at the interface of wound healing. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 11, p. 10-pg., . (15/20206-8)
MEIRELLES, LINDOLFO DA SILVA; WIDERA, DARIUS; BOLONTRADE, MARCELA F.. Current progress in mesenchymal stem/stromal cell research, volume II. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 11, p. 2-pg., . (15/20206-8)
FREITAS VIEIRA, JULIANA MAIRA; ZAMPRONI, LAURA NICOLETI; WENDT, CAMILA H. C.; DE MIRANDA, KILDARE ROCHA; LINDOSO, RAFAEL SOARES; HAN, SANG WON. Overexpression of mir-135b and mir-210 in mesenchymal stromal cells for the enrichment of extracellular vesicles with angiogenic factors. PLoS One, v. 17, n. 8, p. 19-pg., . (18/21072-3, 15/20206-8)
DA SILVA MEIRELLES, LINDOLFO; BIEBACK, KAREN; BOLONTRADE, MARCELA F.. Editorial: Current Progress in Mesenchymal Stem/Stromal Cell Research. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 9, p. 2-pg., . (15/20206-8)
CARVALHO, BRUNA G.; VIT, FRANCIELE F.; CARVALHO, HERNANDES F.; HAN, SANG W.; DE LA TORRE, LUCIMARA G.. Recent advances in co-delivery nanosystems for synergistic action in cancer treatment. JOURNAL OF MATERIALS CHEMISTRY B, v. 9, n. 5, p. 1208-1237, . (18/18523-3, 18/19537-8, 15/20206-8)

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