Capsule stiffness regulates the efficiency of pancreatic differentiation of human embryonic stem cells

Richardson, Thomas; Barner, Sierra; Candiello, Joseph; Kumta, Prashant N.; Banerjee, Ipsita

doi:10.1016/j.actbio.2016.02.025

Cited by 57 publications

(43 citation statements)

References 78 publications

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“…This property allowed an aggressive proliferation in the latter, leading to the formation of huge cell-aggregates. On the contrary, the more restrictive matrix of biological microcapsules established a control in cell division (Richardson et al, 2016;Liu et al, 2015). Therefore, it was not the direct effect of osmolarity adjusting agents on cells which evoked so contrasting behavior, but the effect this agents have in the capsule formation process and thus, in the final crosslinking degree of the alginate matrix.…”

Section: Discussionmentioning

confidence: 99%

The role of osmolarity adjusting agents in the regulation of encapsulated cell behavior to provide a safer and more predictable delivery of therapeutics

et al. 2017

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Transplantation of cells within alginate microspheres has been extensively studied for sustained drug delivery. However, the lack of control over cell behavior represents a major concern regarding the efficacy and the safety of the therapy. Here, we demonstrated that when formulating the biosystem, an adequate selection of osmolarity adjusting agents significantly contributes to the regulation of cell responses. Our data showed that these agents interact in the capsule formation process, influencing the alginate crosslinking degree. Therefore, when selecting inert or electrolyte-based osmolarity adjusting agents to encapsulate D1 multipotent mesenchymal stromal cells (MSCs), alginate microcapsules with differing mechanical properties were obtained. Since mechanical forces acting on cells influence their behavior, contrasting cell responses were observed both, in vitro and in vivo. When employing mannitol as an inert osmolarity adjusting agent, microcapsules presented a more permissive matrix, allowing a tumoral-like behavior. This resulted in the formation of enormous cell-aggregates that presented necrotic cores and protruding peripheral cells, rendering the therapy unpredictable, dysfunctional, and unsafe. Conversely, the use of electrolyte osmolarity adjusting agents, including calcium or sodium, provided the capsule with a suitable crosslinking degree that established a tight control over cell proliferation and enabled an adequate therapeutic regimen in vivo. The crucial impact of these agents was confirmed when gene expression studies reported pivotal divergences not only in proliferative pathways, but also in genes involved in survival, migration, and differentiation. Altogether, our results prove osmolarity adjusting agents as an effective tool to regulate cell behavior and obtain safer and more predictable therapies.ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

The role of osmolarity adjusting agents in the regulation of encapsulated cell behavior to provide a safer and more predictable delivery of therapeutics

et al. 2017

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“…We next evaluated the feasibility of modifying the stiffness of the alginate beads within the array by modulating the BaCl 2 (cation) concentration. Our previous work identified a stiffness range of approximately 3–6 kPa to be ideal for cell growth and pancreatic differentiation . To encompass this stiffness range, we formed the alginate array with varying barium concentrations within the same array, ranging from 20 to 500 mM Ba 2+ .…”

Section: Resultsmentioning

confidence: 99%

“…In our earlier published work, we demonstrated the effect of substrate properties using fibrin and alginate, on the differentiation of mouse embryonic stem cells (mESCs) . More recently, we demonstrated the feasibility of pancreatic differentiation of hESCs within alginate capsules; and identified the range of alginate capsule properties supportive of pancreatic maturation . Another important insoluble cue which can influence hPSC differentiation is cell–cell contact, especially in 3D cellular aggregates.…”

Section: Introductionmentioning

confidence: 97%

Development of an Alginate Array Platform to Decouple the Effect of Multiparametric Perturbations on Human Pluripotent Stem Cells During Pancreatic Differentiation

Richardson

Mathew

Candiello

et al. 2018

Biotechnology Journal

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Human embryonic stem cells (hESC)-derived functional cells hold great promise for regenerative cell therapy. Currently approved strategies for clinical translation requires the isolation of the hESCs-derived cells in materials allowing transfer of reagents but preventing integration with the host. However, hESC fate is known to be sensitive to its local microenvironment, both chemical and physical. Given the complexity of hESC response to environmental parameters, it will be important to evaluate the cell response to multiple combinatorial perturbations. Such complex perturbations are best enabled by exploiting high-throughput screening platforms. In this study, the authors report the effect of multivariate perturbations on hESC differentiation, enabled by the development of high throughput 3D alginate array platform. Specifically, the sensitivity of hESC propagation and pancreatic differentiation to substrate properties and cell culture configuration is analyzed. Cellular response to array perturbations is analyzed by quantitative imaging, and cell sensitivity was determined through statistical modeling. The results indicate that configuration is the stronger determinant of hESC proliferation and differentiation, while substrate properties fine-tune the expression around the average levels. This platform allowed for multiparametric perturbations, and in combination with statistical modeling, allows to identify the sensitivity of hESC proliferation and fate to multiparametric modulation.

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“…As material stiffness affects cellular function and fate, [8,9,21,33] microgels with varied stiffness, or even chemical moieties, might be included within the formulation to probe cell growth fate decisions in unique ways. While homogenous particles can be incorporated ubiquitously within the formulation, they could also be segregated to produce sub-regions within the material.…”

Section: Discussionmentioning

confidence: 99%

Clickable Microgel Scaffolds as Platforms for 3D Cell Encapsulation

Caldwell

Campbell

Shekiro

et al. 2017

Adv Healthcare Materials

108

132

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While microporous scaffolds have been increasingly used for regenerative medicine and tissue repair applications, the most common techniques to fabricate these scaffolds use templating or top-down fabrication approaches. Cytocompatible bottom-up assembly methods afford the opportunity to assemble micro-porous systems in the presence of cells and create complex polymer-cell composite systems in situ. Here, microgel building blocks with clickable surface groups were synthesized for the bottom-up fabrication of porous cell-laden scaffolds. The facile nature of assembly allowed for human mesenchymal stem cells to be incorporated throughout the porous scaffold. Particles were designed with mean diameters of approximately 10 μm and 100 μm, and assembled to create varied microenvironments. The resulting pore sizes and their distribution significantly altered cell morphology and cytoskeletal formation. This microgel-based system provides numerous tunable properties, which can be used to control multiple aspects of cellular growth and development, as well as providing the ability to recapitulate various biological interfaces.

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Capsule stiffness regulates the efficiency of pancreatic differentiation of human embryonic stem cells

Cited by 57 publications

References 78 publications

The role of osmolarity adjusting agents in the regulation of encapsulated cell behavior to provide a safer and more predictable delivery of therapeutics

The role of osmolarity adjusting agents in the regulation of encapsulated cell behavior to provide a safer and more predictable delivery of therapeutics

Development of an Alginate Array Platform to Decouple the Effect of Multiparametric Perturbations on Human Pluripotent Stem Cells During Pancreatic Differentiation

Clickable Microgel Scaffolds as Platforms for 3D Cell Encapsulation

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