Pluripotent Stem Cell-Derived Pancreatic Progenitors and β-Like Cells for Type 1 Diabetes Treatment

Sambathkumar, Rangarajan; Migliorini, Adriana; Nostro, M. Cristina

doi:10.1152/physiol.00026.2018

Cited by 22 publications

(20 citation statements)

References 89 publications

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“…We next investigated the expression profile of Cx43 in ESCs cultured under conditions that direct their differentiation toward the pancreatic cell lineages (D’Amour et al., 2006, Xu et al., 2011, Rezania et al., 2014, Pagliuca et al., 2014, Russ et al., 2015, Nostro et al., 2015, Sambathkumar et al., 2018, Sneddon et al., 2018) (Figure 2A). These studies uncovered a progressive upregulation of Cx43, both at the transcriptional (Figure 2B) and translational levels (Figures 2C and 2D), that peaked at the DE and PGT stages of ESC differentiation, followed by a sudden drop at the posterior foregut (PF) stage.…”

Section: Resultsmentioning

confidence: 99%

Connexin 43 Functions as a Positive Regulator of Stem Cell Differentiation into Definitive Endoderm and Pancreatic Progenitors

et al. 2019

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Summary Efficient stem cell differentiation into pancreatic islet cells is of critical importance for the development of cell replacement therapies for diabetes. Here, we identify the expression pattern of connexin 43 (Cx43), a gap junction (GJ) channel protein, in human embryonic stem cell (hESC)-derived definitive endoderm (DE) and primitive gut tube cells, representing early lineages for posterior foregut (PF), pancreatic progenitors (PP), pancreatic endocrine progenitors (PE), and islet cells. As the function of GJ channels is dependent on their gating status, we tested the impact of supplementing hESC-derived PP cell cultures with AAP10, a peptide that promotes Cx43 GJ channel opening. We found that this treatment promotes the expression of DE markers FoxA2 and Sox17, leads to a more efficient derivation of DE, and improves the yield of PF, PP, and PE cells. These results demonstrate a functional involvement of GJ channels in the differentiation of embryonic stem cells into pancreatic cell lineages.

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Section: Resultsmentioning

confidence: 99%

Connexin 43 Functions as a Positive Regulator of Stem Cell Differentiation into Definitive Endoderm and Pancreatic Progenitors

et al. 2019

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“…This strategy would reduce costs and allow higher batch sizes. However, recent animal studies show that teratomas may occur in stem cell‐based devices and that a purification step is advisable for safety . In order to overcome the scalability and yield limitations of MACS, economic assessment of other DSP systems evaluated for PSCs and PSC‐derived differentiated cell types, such as aqueous two‐phase separation and tangential flow filtration, could be a future strategy to increase the annual demand and batch size without compromising the facility footprint.…”

Section: Discussionmentioning

confidence: 99%

“…The scalability of the process to 3D suspension platforms, such as spinners [9,11,39] and bioreactors, [40,41] either in aggregate or microcarrier-based platforms, could improve both the expansion and differentiation rates and yields by providing a more similar environment to the native niche, combined with better metabolite and growth factor control. [36,[42][43][44] While the stem cell-based therapy would bring an added quality of life to most patients, the transplantation has very high upfront costs in comparison with the continuous administration of insulin. The finding that the therapy would be cost saving for patients for whom ESRD is avoided is consistent with the current clinical development of devices allowing direct vascularization for the treatment of patients with a high risk of ESRD.…”

Section: Discussionmentioning

confidence: 99%

“…The costs of differentiation can be mitigated by the development of more efficient directed differentiation and media exchange protocols at a larger scale. The scalability of the process to 3D suspension platforms, such as spinners and bioreactors, either in aggregate or microcarrier‐based platforms, could improve both the expansion and differentiation rates and yields by providing a more similar environment to the native niche, combined with better metabolite and growth factor control …”

Section: Discussionmentioning

confidence: 99%

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Bringing Stem Cell‐Based Therapies for Type 1 Diabetes to the Clinic: Early Insights from Bioprocess Economics and Cost‐Effectiveness Analysis

Bandeiras

Cabral

Gabbay

et al. 2019

Biotechnology Journal

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Differentiation of pluripotent stem cells (PSCs) into β cells could provide insulin independence for type 1 diabetes (T1D) patients. This approach would reduce the clinical complications that most patients managed on intensive insulin therapy (IIT) face. However, bottlenecks of PSC manufacturing and limited engraftment of encapsulated cells hinder the long‐term effectiveness of these therapies. A bioprocess decision‐support tool is combined with a disease state‐transition model to evaluate the cost‐effectiveness of the stem cell‐based therapy against IIT. Clinical effectiveness is assessed in quality‐adjusted life years (QALYs). Manufacturing costs per patient reduce from $430 000 to $160 000 with optimization of batch size and annual demand. For 96% of the patients, cell therapy improves the quality of life compared to IIT. Cost savings are achieved for 2% of the population through prevention of renal disease. The therapy is cost‐effective for 3.4% of patients when a willingness to pay (WTP) of up to $150 000 per QALY is considered. A 75% cost reduction in the cell therapy price increases cost‐effectiveness likelihood to 51% at $100 000 per QALY. This study highlights the need for scalable manufacturing platforms for stem cell therapies, as well as to prioritizing access to the therapy to patients with an increased likelihood of costly complications.

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“…[60,63,64] Pluripotent and multipotent stem cells differentiated into β-cells in vitro are a sustainable and scalable source of insulinproducing cells for transplantation, but also for the study of β-cell developmental biology, physiology, pathology, and toxicology. [65,66] from hPSCs using exquisitely tuned multistep combinations of growth factors and small molecules in 2D monolayers or 3D organoids. Some of these well-developed protocols require many weeks (some up to 8 weeks) of in vitro culture to achieve β-cell organoids displaying most mature β-cell specific markers and function.…”

Section: Types Of β-Cell Organoidsmentioning

confidence: 99%

Engineered Biomaterials for Enhanced Function of Insulin‐Secreting β‐Cell Organoids

Hunckler

Garcı́a

2020

Adv Funct Materials

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Insulin-secreting β-cell organoids comprise many types of cells, including primary islets, pseudoislets, immortalized cell lines, and stem cell-derived aggregates. Successful maintenance and long-term culture of these β-cell organoids are critical for many translational applications, such as patient-specific disease modeling, drug screening, understanding β-cell physiology, and cell-based therapies to treat diabetes. Due to the mechanical and chemical insult to islets during isolation, islet viability and function are decreased. Partial restoration of the islet microenvironment through engineered biomaterials can improve islet survival and function in in vitro culture and in vivo transplantation. Natural and synthetic biomaterials can be engineered to improve the function of β-cell organoids and promote maturation of stem cell-derived β-cell organoids. Improved function and maturation of β-cell organoids will likely lead to improved transplant outcomes, but will also enable better models for physiology, disease modeling, and toxicology studies for type 1 and type 2 diabetes mellitus. The goal of this review is to highlight the diverse array of biomaterials used to enhance the in vitro and in vivo function and maturation of β-cell organoids.

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Pluripotent Stem Cell-Derived Pancreatic Progenitors and β-Like Cells for Type 1 Diabetes Treatment

Cited by 22 publications

References 89 publications

Connexin 43 Functions as a Positive Regulator of Stem Cell Differentiation into Definitive Endoderm and Pancreatic Progenitors

Connexin 43 Functions as a Positive Regulator of Stem Cell Differentiation into Definitive Endoderm and Pancreatic Progenitors

Bringing Stem Cell‐Based Therapies for Type 1 Diabetes to the Clinic: Early Insights from Bioprocess Economics and Cost‐Effectiveness Analysis

Engineered Biomaterials for Enhanced Function of Insulin‐Secreting β‐Cell Organoids

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