Lucia Catani1, Daria Sollazzo2, Elisa Bianchi3, Marilena Ciciarello2, Chiara Antoniani2, Licia Foscoli2, Paolo Caraceni4, Ferdinando Antonino Giannone5, Maurizio Baldassarre5, Rosaria Giordano6, Tiziana Montemurro6, Elisa Montelatici6, Antonia D'Errico7, Pietro Andreone7, Valeria Giudice8, Antonio Curti2, Rossella Manfredini3, Roberto Massimo Lemoli9. 1. Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy. Electronic address: lucia.catani@unibo.it. 2. Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," University of Bologna, Bologna, Italy. 3. Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy. 4. Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; Center for Applied Biomedical Research (C.R.B.A.), Azienda Ospedaliero/Universitaria di Bologna, Bologna, Italy. 5. Center for Applied Biomedical Research (C.R.B.A.), Azienda Ospedaliero/Universitaria di Bologna, Bologna, Italy. 6. Cell Factory, Unit of Cellular Therapy and Cryobiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy. 7. Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. 8. Immunohematology Service and Blood Bank-Azienda Ospedaliero/Universitaria di Bologna, Bologna, Italy. 9. Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.
Abstract
BACKGROUND AIMS: Growing evidence supports the therapeutic potential of bone marrow (BM)-derived stem/progenitor cells for end-stage liver disease (ESLD). We recently demonstrated that CD133+ stem/progenitor cell (SPC) reinfusion in patients with ESLD is feasible and safe and improve, albeit transiently, liver function. However, the mechanism(s) through which BM-derived SPCs may improve liver function are not fully elucidated. METHODS: Here, we characterized the circulating SPCs compartment of patients with ESLD undergoing CD133+ cell therapy. Next, we set up an in vitro model mimicking SPCs/liver microenvironment interaction by culturing granulocyte colony-stimulating factor (G-CSF)-mobilized CD133+and LX-2 hepatic stellate cells. RESULTS: We found that patients with ESLD show normal basal levels of circulating hematopoietic and endothelial progenitors with impaired clonogenic ability. After G-CSF treatment, patients with ESLD were capable to mobilize significant numbers of functional multipotent SPCs, and interestingly, this was associated with increased levels of selected cytokines potentially facilitating SPC function. Co-culture experiments showed, at the molecular and functional levels, the bi-directional cross-talk between CD133+ SPCs and human hepatic stellate cells LX-2. Human hepatic stellate cells LX-2 showed reduced activation and fibrotic potential. In turn, hepatic stellate cells enhanced the proliferation and survival of CD133+ SPCs as well as their endothelial and hematopoietic function while promoting an anti-inflammatory profile. DISCUSSION: We demonstrated that the interaction between CD133+ SPCs from patients with ESLD and hepatic stellate cells induces significant functional changes in both cellular types that may be instrumental for the improvement of liver function in cirrhotic patients undergoing cell therapy.
BACKGROUND AIMS: Growing evidence supports the therapeutic potential of bone marrow (BM)-derived stem/progenitor cells for end-stage liver disease (ESLD). We recently demonstrated that CD133+ stem/progenitor cell (SPC) reinfusion in patients with ESLD is feasible and safe and improve, albeit transiently, liver function. However, the mechanism(s) through which BM-derived SPCs may improve liver function are not fully elucidated. METHODS: Here, we characterized the circulating SPCs compartment of patients with ESLD undergoing CD133+ cell therapy. Next, we set up an in vitro model mimicking SPCs/liver microenvironment interaction by culturing granulocyte colony-stimulating factor (G-CSF)-mobilized CD133+and LX-2 hepatic stellate cells. RESULTS: We found that patients with ESLD show normal basal levels of circulating hematopoietic and endothelial progenitors with impaired clonogenic ability. After G-CSF treatment, patients with ESLD were capable to mobilize significant numbers of functional multipotent SPCs, and interestingly, this was associated with increased levels of selected cytokines potentially facilitating SPC function. Co-culture experiments showed, at the molecular and functional levels, the bi-directional cross-talk between CD133+ SPCs and human hepatic stellate cells LX-2. Human hepatic stellate cells LX-2 showed reduced activation and fibrotic potential. In turn, hepatic stellate cells enhanced the proliferation and survival of CD133+ SPCs as well as their endothelial and hematopoietic function while promoting an anti-inflammatory profile. DISCUSSION: We demonstrated that the interaction between CD133+ SPCs from patients with ESLD and hepatic stellate cells induces significant functional changes in both cellular types that may be instrumental for the improvement of liver function in cirrhotic patients undergoing cell therapy.