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Encapsulated human multipotent mesenchymal stromal cells maintain differentiation capacity and have anti-fibrotic effects

Raphael Meier^1,2, Redouan Mahou⁴, Philippe Morel^1,2, Yannick Muller^1,2, Panayiotis Christofilopoulos³, Christine Wandrey⁴, Carmen Gonelle-Gispert², Léo Bühler^1,2

¹Visceral and Transplantation Surgery, Geneva University Hospitals, Geneva; ²Surgical Research Unit, University of Geneva Medical School, Geneva; ³Orthopaedics and Trauma Surgery, Geneva University Hospitals, Geneva; ⁴Institute of Bioengineering and Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Introduction: Human multipotent mesenchymal stromal cells (MSC) secrete anti-inflammatory cytokines such IL1ra. We have tested the viability, proliferation and differentiation capacity of human MSC after microencapsulation in vitro. To test the anti-inflammatory effect in vivo, we transplanted encapsulated human MSC into mice with liver fibrosis.

Materials and methods: Human bone marrow-derived MSC were isolated from femoral heads of patients undergoing total hip replacement. MSC (at passage 2) were microencapsulated using a novel alginate-poly(ethylene glycol) hybrid hydrogel (0.4 mm). In vitro, we analyzed viability, proliferation, and differentiation capacity of encapsulated MSC. In vivo, we transplanted encapsulated MSC or empty capsules into the peritoneum of DBA-1 mice with liver fibrosis induced by bile duct ligation. Liver fibrosis was evaluated after 5 days by quantification of collagen deposition on liver sections using the MetaMorph software.

Results: The viability and proliferation of encapsulated MSC was similar when compared to non-encapsulated MSC. When exposed to specific medium, MSC maintained their capacity to differentiate into adipocytes within the capsules (14.8% ± 3.7 of MSC after two weeks of culture versus 18.02 ± 7.3% among non-encapsulated cells, p= 0.7). In vivo, encapsulated MSC were viable and vimentin positive at 26 days after intraperitoneal transplantation in DBA-1 mice. When transplanted in mice with bile duct ligation, encapsulated MSC significantly delayed the development of liver fibrosis compared to empty capsules, i.e. the collagen deposition per hepatocyte was reduced from 3.6% ± 0.4% to 2.4% ± 0.2% (p = 0.029).

Conclusion: Transplantation of encapsulated MSC represents a promising strategy for local and systemic delivery of anti-inflammatory and immuomodulatory molecules secreted by MSC.