Cited by 7Pancreatic function and diabetesPluripotent Stem Cells ResearchDiabetes and associated disorders

Identifying and optimizing critical process parameters for large-scale manufacturing of iPSC derived insulin-producing β-cells

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Yehya, Haneen, Wells, Alexandra, Majcher, Michael, Nakhwa, Dhruv, King, Ryan, Senturk, Faruk, Padmanabhan, Roshan, Jensen, Jan +1 more·2024·Stem Cell Research & Therapy

Published version of a preprint

Abstract

BACKGROUND: Type 1 diabetes, an autoimmune disorder leading to the destruction of pancreatic β-cells, requires lifelong insulin therapy. Islet transplantation offers a promising solution but faces challenges such as limited availability and the need for immunosuppression. Induced pluripotent stem cells (iPSCs) provide a potential alternative source of functional β-cells and have the capability for large-scale production. However, current differentiation protocols, predominantly conducted in hybrid or 2D settings, lack scalability and optimal conditions for suspension culture. METHODS: We examined a range of bioreactor scaleup process parameters and quality target product profiles that might affect the differentiation process. This investigation was conducted using an optimized High Dimensional Design of Experiments (HD-DoE) protocol designed for scalability and implemented in 0.5L (PBS-0.5 Mini) vertical wheel bioreactors. RESULTS: A three stage suspension manufacturing process is developed, transitioning from adherent to suspension culture, with TB2 media supporting iPSC growth during scaling. Stage-wise optimization approaches and extended differentiation times are used to enhance marker expression and maturation of iPSC-derived islet-like clusters. Continuous bioreactor runs were used to study nutrient and growth limitations and impact on differentiation. The continuous bioreactors were compared to a Control media change bioreactor showing metabolic shifts and a more β-cell-like differentiation profile. Cryopreserved aggregates harvested from the runs were recovered and showed maintenance of viability and insulin secretion capacity post-recovery, indicating their potential for storage and future transplantation therapies. CONCLUSION: This study demonstrated that stage time increase and limited media replenishing with lactate accumulation can increase the differentiation capacity of insulin producing cells cultured in a large-scale suspension environment.

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  • Treating many people with type 1 diabetes will require substantial scale-up of cell manufacturing and other changes, such as potentially shortening the duration of in-vitro steps to reduce cost and increase efficiency.

    “Treating many people with type 1 diabetes will require substantial scaleup of cell manufacturing and other changes, such as potentially shortening the duration of invitro steps to reduce cost and increase efficiency.78,79”

    From The future of type 1 diabetes therapy (2025) · cites this paper as [79]

    The Background and Discussion support the need to scale up manufacturing to produce enough cells for type 1 diabetes treatment. But the Discussion reports that extending differentiation stages improved desired markers and proposes reducing media replenishment to offset the added cost; it does not support shortening the in-vitro stages as the efficiency measure. (LLM, conf=0.89)

    Experimental — accuracy not yet measured
  • Approximately 1 billion pancreatic progenitor cells are estimated to be required per person, although this number could be less if more mature cells are used.

    “Approximately 1 billion pancreatic progenitor cells are estimated to be required per person, although this number could be less if more mature cells are used.”

    From The future of type 1 diabetes therapy (2025) · cites this paper as [79]

    The Discussion estimates that around 1 billion β-cells are needed to treat a patient with type 1 diabetes. It does not give that estimate for pancreatic progenitor cells or say that using more mature cells could reduce the number required. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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Authors
Yehya, H., Wells, A., Majcher, M., Nakhwa, D., King, R., Senturk, F., Padmanabhan, R., Jensen, J., & Bukys, M. A.
Affiliations
Cleveland State University (US)
Corresponding author
Bukys, Michael A.
Venue
Stem Cell Research & Therapy
Published
2024-11-09
Volume
15
Issue
1
Pages
408-408
ISSN
1757-6512 (ISSN-L)
OpenAlex
W4404199370
Cited by
7
References
62
Citations by year
2026: 4 · 2025: 3
FWCI
2.95
Type
journal article
Language
en
Open access
Locations
  • Stem Cell Research & Therapy (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Cleveland State University
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
insulin-producing cells, type 1 diabetes, islet transplantation, suspension culture, bioreactor scale-up, vertical-wheel bioreactor, islet-like clusters, lactate accumulation, continuous bioreactor, cryopreservation, insulin secretion, quality target product profile
MeSH terms
Cell Differentiation, Cells, Cultured, Humans, Insulin, Cell Culture Techniques, Bioreactors, Insulin-Secreting Cells, Induced Pluripotent Stem Cells

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