Sulfated Alginate Reduces Pericapsular Fibrotic Overgrowth on Encapsulated cGMP-Compliant hPSC-Hepatocytes in Mice

Abstract

Intra-peritoneal placement of alginate encapsulated human induced pluripotent stem cell-derived hepatocytes (hPSC-Heps) represents a potential new bridging therapy for acute liver failure. One of the rate-limiting steps that needs to be overcome to make such a procedure more efficacious and safer is to reduce the accumulation of fibrotic tissue around the encapsulated cells to allow the free passage of relevant molecules in and out for metabolism. Novel chemical compositions of alginate afford the possibility of achieving this aim. We accordingly used sulfated alginate and demonstrated that this material reduced fibrotic overgrowth whilst not impeding the process of encapsulation nor cell function. Cumulatively, this suggests sulfated alginate could be a more suitable material to encapsulate hPSC-hepatocyte prior to human use.

Microencapsulated Hepatocytes Differentiated from Human Induced Pluripotent Stem Cells: Optimizing 3D Culture for Tissue Engineering Applications

“…Several research groups have encapsulated pluripotent stem cells and investigated hepatocyte differentiation, though their analysis of liver functions has been limited [ 34 , 35 , 36 , 37 ]. Recently, Syanda et al, evaluated the encapsulation of hESC-derived hepatocyte aggregates in modified alginate and demonstrated the advantages of using this approach for transplantation in a mouse model [ 26 ]. However, they did not explore the effects of alginate encapsulation on the maturity and functionality of the hepatocytes thus differentiated.…”

“…Furthermore, several studies have demonstrated the beneficial effects of encapsulation on the enhancement of viability and metabolic performance for prolonged periods [ 22 , 23 ]. In addition, alginate beads could easily be cryopreserved and thus rapidly available for use [ 24 , 25 , 26 ]. However, this technology has not been widely explored in hepatocyte differentiation, and various parameters still need to be studied.…”

MS-proteomics provides insight into the host responses towards alginate microspheres

“…In summary, the previous sections have highlighted proteins that may have an impact on the PFO responses seen in vivo [ 10 ], with a particular focus on HiG and SA. Sulfated alginate reduces the fibrotic host response towards empty and cell-containing microbeads compared to high G alginate [ 3 , 10 ], demonstrating the significance of using biomaterials with low inflammatory potential in cellular therapies that depend on the free diffusion of oxygen and nutrients to encapsulated cells. In this study, the binding of inhibitors (e.g.…”

“…The use of alginate hydrogel microspheres for immunoisolation in cell therapy holds great promise for treating various medical conditions, e.g. type 1 diabetes or acute liver failure, mitigating the need for systemic immunosuppressive treatment after graft transplantation [ [1] , [2] , [3] ]. However, implantation of biomaterials may result in acute and chronic inflammatory responses that lead to fibrotic tissue development, as part of the foreign body response [ 4 ].…”

Multi-step Strategies Toward Regioselectively Sulfated M-Rich Alginates

“…A refractive index increment (d n /d c ) value of 0.138 mL/g, as reported for water solutions of native, sulfated, or selenylated polymannuronate derivatives, was used for calculations. It is worth noting that the molecular weight data from SEC-TDA varied less than 10% when using 0.13–0.15 mL/g d n /d c , which is the range reported for unmodified and sulfated alginates (M-rich, G-rich, and unenriched species). − An appropriate amount of each AS sample was dissolved in pure water and stirred at 25 °C overnight. The solution was then centrifuged, filtered on 0.22 μm filters, and analyzed for hydrodynamic characterization in triplicate.…”