Retinoic acid generated by <i>Raldh2</i> in mesoderm is required for mouse dorsal endodermal pancreas development

Molotkov, Andrei; Molotkova, Natalia; Duester, Gregg

doi:10.1002/dvdy.20256

Cited by 188 publications

(151 citation statements)

References 34 publications

Supporting

Mentioning

139

Contrasting

Order By: Relevance

“…Because we used a relatively high concentration (20%) of serum during EB formation (three-dimensional differentiation), the optimal range of serum concentrations for endodermal differentiation seems to vary depending on the culture conditions. RA generated from lateral plate mesoderm has recently been reported to control Pdx1 expression in early pancreatic development in mice and zebrafish [36][37][38]. Our study demonstrated that RA treatment at the end of EB formation efficiently upregulated PDX1 expression, together with FOXA2 and SOX17 expression, while strongly downregulating the expression of MIXL1 and T, both of which were previously used as markers of the mesendodermal differentiation of ESCs [35].…”

Section: Discussionsupporting

confidence: 59%

Directed differentiation of human embryonic stem cells towards a pancreatic cell fate

et al. 2007

View full text Add to dashboard Cite

Aims/hypothesis The relative lack of successful pancreatic differentiation of human embryonic stem cells (hESCs) may suggest that directed differentiation of hESCs into definitive endoderm and subsequent commitment towards a pancreatic fate are not readily achieved. The aim of this study was to investigate whether sequential exposure of hESCs to epigenetic signals that mimic in vivo pancreatic development can efficiently generate pancreatic endodermal cells, and whether these cells can be further matured and reverse hyperglycaemia upon transplantation. Materials and methods The hESCs were sequentially treated with serum, activin and retinoic acid (RA) during embryoid body formation. The patterns of gene expression and protein production associated with embryonic germ layers and pancreatic endoderm were analysed by RT-PCR and immunostaining. The developmental competence and function of hESC-derived PDX1-positive cells were evaluated after in vivo transplantation. Results Sequential treatment with serum, activin and RA highly upregulated the expression of the genes encoding forkhead box protein A2 (FOXA2), SRY-box containing gene 17 (SOX17), pancreatic and duodenal homeobox 1 (PDX1) and homeobox HB9 (HLXB9). The population of pancreatic endodermal cells that produced PDX1 was significantly increased at the expense of ectodermal differentiation, and a subset of the PDX1-positive cells also produced FOXA2, caudal-type homeobox transcription factor 2 (CDX2), and nestin (NES). After transplantation, the PDX1-positive cells further differentiated into mature cell types producing insulin and glucagon, resulting in amelioration of hyperglycaemia and weight loss in streptozotocin-treated diabetic mice. Conclusions/interpretation Our strategy allows the progressive differentiation of hESCs into pancreatic endoderm capable of generating mature pancreatic cell types that function in vivo. These findings may establish the basis of further investigations for the purification of transplantable islet progenitors derived from hESCs.

show abstract

Section: Discussionsupporting

confidence: 59%

Directed differentiation of human embryonic stem cells towards a pancreatic cell fate

et al. 2007

View full text Add to dashboard Cite

show abstract

“…The level of conservation in determining pancreatic boundary establishment by Cdx4 and Cyp26a1 across vertebrate species has not been determined. In RALDH2 null mice, which lack a critical RA-synthesizing enzyme, the dorsal pancreas fails to bud and the early glucagon þ cells do not develop (Molotkov et al, 2005;Martin et al, 2005). This dorsal pancreas agenesis phenotype in RALDH2 null mice is reminiscent of the pancreas phenotype observed in Islet1 (Isl1) or N-cadherin (Esni et al, 2001) knockout mice.…”

Section: Figmentioning

confidence: 92%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

524

594

View full text Add to dashboard Cite

Pancreas oganogenesis comprises a coordinated and highly complex interplay of signaling events and transcriptional networks that guide a step-wise process of organ development from early bud specification all the way to the final mature organ state. Extensive research on pancreas development over the last few years, largely driven by a translational potential for pancreatic diseases (diabetes, pancreatic cancer, and so on), is markedly advancing our knowledge of these processes. It is a tenable goal that we will one day have a clear, complete picture of the transcriptional and signaling codes that control the entire organogenetic process, allowing us to apply this knowledge in a therapeutic context, by generating replacement cells in vitro, or perhaps one day to the whole organ in vivo. This review summarizes findings in the past 5 years that we feel are amongst the most significant in contributing to the deeper understanding of pancreas development. Rather than try to cover all aspects comprehensively, we have chosen to highlight interesting new concepts, and to discuss provocatively some of the more controversial findings or proposals. At the end of the review, we include a perspective section on how the whole pancreas differentiation process might be able to be unwound in a regulated fashion, or redirected, and suggest linkages to the possible reprogramming of other pancreatic cell-types in vivo, and to the optimization of the forward-directed-differentiation of human embryonic stem cells (hESC), or induced pluripotential cells (iPSC), towards mature b-cells. Developmental Dynamics 240:530-565,

show abstract

“…Mouse embryos deficient for the RA-synthesizing enzyme retinaldehyde dehydrogenase 2 (RALDH2), if rescued from early lethality by maternal RA, lack active RA signaling in the foregut region. In the resulting mutants, development of the lungs (Desai et al, 2004;Wang et al, 2006), stomach, duodenum, liver (Wang et al, 2006), and dorsal pancreas (Molotkov et al, 2005) is severely affected.…”

Section: In Vitro Pancreas-induction Systems Using Undifferentiated Xmentioning

confidence: 99%

In vitro organogenesis from undifferentiated cells in Xenopus

Asashima

Ito

Chan

et al. 2009

Developmental Dynamics

View full text Add to dashboard Cite

Amphibians have been used for over a century as experimental animals. In the field of developmental biology in particular, much knowledge has been accumulated from studies on amphibians, mainly because they are easy to observe and handle. Xenopus laevis is one of the most intensely investigated amphibians in developmental biology at the molecular level. Thus, Xenopus is highly suitable for studies on the mechanisms of organ differentiation from not only a single fertilized egg, as in normal development, but also from undifferentiated cells, as in the case of in vitro organogenesis. Based on the established in vitro organogenesis methods, we have identified many genes that are indispensable for normal development in various organs. These experimental systems are useful for investigations of embryonic development and for advancing regenerative medicine. Developmental Dynamics 238:1309 -1320, 2009.

show abstract

Retinoic acid generated by Raldh2 in mesoderm is required for mouse dorsal endodermal pancreas development

Cited by 188 publications

References 34 publications

Directed differentiation of human embryonic stem cells towards a pancreatic cell fate

Directed differentiation of human embryonic stem cells towards a pancreatic cell fate

Pancreas organogenesis: From bud to plexus to gland

In vitro organogenesis from undifferentiated cells in Xenopus

Contact Info

Product

Resources

About