Influence of in vitro and in vivo oxygen modulation on β cell differentiation from human embryonic stem cells

Sirlene Cechin, Silvia Álvarez-Cubela, Jaime A. Giraldo, Ruth Molano, Susana Villate, Camillo Ricordi, Antonello Pileggi, Luca A Inverardi, Christopher Fraker, Juan Dominguez-Bendala

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The possibility of using human embryonic stem (hES) cell-derived β cells as an alternative to cadaveric islets for the treatment of type 1 diabetes is now widely acknowledged. However, current differentiation methods consistently fail to generate meaningful numbers of mature, functional β cells. In order to address this issue, we set out to explore the role of oxygen modulation in the maturation of pancreatic progenitor (PP) cells differentiated from hES cells. We have previously determined that oxygenation is a powerful driver of murine PP differentiation along the endocrine lineage of the pancreas. We hypothesized that targeting physiological oxygen partial pressure (pO2) levels seen in mature islets would help the differentiation of PP cells along the β-cell lineage. This hypothesis was tested both in vivo (by exposing PP-transplanted immunodeficient mice to a daily hyperbaric oxygen regimen) and in vitro (by allowing PP cells to mature in a perfluorocarbon-based culture device designed to carefully adjust pO2 to a desired range). Our results show that oxygen modulation does indeed contribute to enhanced maturation of PP cells, as evidenced by improved engraftment, segregation of α and β cells, body weight maintenance, and rate of diabetes reversal in vivo, and by elevated expression of pancreatic endocrine makers, β-cell differentiation yield, and insulin production in vitro. Our studies confirm the importance of oxygen modulation as a key variable to consider in the design of β-cell differentiation protocols and open the door to future strategies for the transplantation of fully mature β cells.

Original languageEnglish
Pages (from-to)277-289
Number of pages13
JournalStem cells translational medicine
Volume3
Issue number3
DOIs
StatePublished - Jan 1 2014

Fingerprint

Cell Differentiation
Oxygen
Stem Cells
Fluorocarbons
Endocrine Cells
Partial Pressure
Cell Lineage
Type 1 Diabetes Mellitus
Islets of Langerhans
Transplantation
In Vitro Techniques
Human Embryonic Stem Cells
Insulin
Equipment and Supplies

Keywords

  • Cell transplantation
  • Cellular therapy
  • Developmental biology
  • Diabetes
  • Embryonic stem cells
  • Microenvironment
  • Pancreas
  • Pancreatic differentiation

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology

Cite this

Influence of in vitro and in vivo oxygen modulation on β cell differentiation from human embryonic stem cells. / Cechin, Sirlene; Álvarez-Cubela, Silvia; Giraldo, Jaime A.; Molano, Ruth; Villate, Susana; Ricordi, Camillo; Pileggi, Antonello; Inverardi, Luca A; Fraker, Christopher; Dominguez-Bendala, Juan.

In: Stem cells translational medicine, Vol. 3, No. 3, 01.01.2014, p. 277-289.

Research output: Contribution to journalArticle

Cechin, Sirlene ; Álvarez-Cubela, Silvia ; Giraldo, Jaime A. ; Molano, Ruth ; Villate, Susana ; Ricordi, Camillo ; Pileggi, Antonello ; Inverardi, Luca A ; Fraker, Christopher ; Dominguez-Bendala, Juan. / Influence of in vitro and in vivo oxygen modulation on β cell differentiation from human embryonic stem cells. In: Stem cells translational medicine. 2014 ; Vol. 3, No. 3. pp. 277-289.
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