Duodeno-pancreatic endoderm cell produces primary multipotent pancreatic progenitor cell (MPC) in the dorsal pancreatic bud (Jennings et al. 2013). Large-scale scRNA-seq and ATAC-seq of human embryonic pancreas indicate that, in addition to the shared markers, dorsal MPCs express NRF21 and SIM1 not expressed in ventral MPCs, and show a higher expression of genes related to WNT signaling (Ma et al. 2023). Single cell mouse transcriptomics analysis implies that there is a distinction in pluripotency between early and late MPCs (Yu et al. 2019). Dorsal MPCs, as well as early and late MPCs, may be annotated when more data becomes available.
Primary MPCs are crucial cells in the early development of the pancreas, capable of giving rise to all the major cell types within the organ, including endocrine, exocrine, and ductal cells (reviewed in Pan and Wright 2011, Domínguez-Bendala et al. 2019).
Primary MPCs are characterized by expression of the following markers:
Table of markers of primary multipotent pancreatic progenitor cells.
| Marker (protein/RNA) | Literature Reference | CellMarker database – RNA/Protein (Hu et al. 2022) | PanglaoDB – RNA (Franzén et al. 2019) |
|---|
| FOXA2 (protein, RNA) | Johannesson et al. 2009 (protein, RNA: hESC-derived MPCs);
Xu et al. 2011 (protein, RNA: hESC-derived MPCs);
Jennings et al. 2013 (protein: pancreatic bud cells at Carnegie stage CS13, corresponding to day ~32 post-conception, during post-conception week PCW5 or gestational week GW7);
Cebola et al. 2015 (RNA: in vivo MPCs from human embryonic pancreas at CS16-18, corresponding to days 38 to 44 post-conception during PCW6-7 or GW8-9); | No | No |
| GATA4 (protein, RNA) | Jennings et al. 2013 (protein: pancreatic bud cells at CS13);
Veres et al. 2019 (RNA: hESC-derived MPCs);
Jiang et al. 2021 (RNA: hPSC-derived MPCs); | No | No |
| GATA6 (RNA) | Cebola et al. 2015 (RNA: in vivo MPCs from human embryonic pancreas at CS16-18);
Veres et al. 2019 (RNA: hESC-derived MPCs);
Olaniru et al. 2023 (RNA: GW8 of human embryonal pancreas); | No | No |
| HNF1B (RNA) | Cebola et al. 2015 (RNA: in vivo MPCs from human embryonic pancreas at CS16-18);
Veres et al. 2019 (RNA: hESC-derived MPCs);
El-Khairi et al. 2021 (protein, RNA: hiPSC-derived MPCs);
Olaniru et al. 2023 (RNA: GW8 of human embryonal pancreas); | No | No |
| NKX6-1 (protein, RNA) | Jennings et al. 2013 (protein: pancreatic bud cells at CS13);
Gage et al. 2015 (protein, RNA: hESC-derived MPCs);
Cebola et al. 2015 (RNA: in vivo MPCs from human embryonic pancreas at CS16-18);
Veres et al. 2019 (RNA: hESC-derived MPCs);
Olaniru et al. 2023 (RNA: GW8 of human embryonal pancreas); | No | No |
| ONECUT1 (HNF6) (protein, RNA) | Johanneson et al. 2009 (protein, RNA: hESC-derived MPCs);
Cebola et al. 2015 (RNA: in vivo MPCs from human embryonic pancreas at CS16-18);
Veres et al. 2019 (RNA: hESC-derived MPCs);
Jiang et al. 2021 (RNA: hPSC-derived MPCs); | No | Yes |
| PDX1 (protein, RNA) | Johannesson et al. 2009 (protein, RNA: hESC-derived MPCs);
Xu et al. 2011 (protein, RNA: hESC-derived MPCs);
Jennings et al. 2013 (protein: pancreatic bud cells at CS13);
Gage et al. 2015 (protein, RNA: hESC-derived MPCs);
Cebola et al. 2015 (RNA: in vivo MPCs from human embryonic pancreas at CS16-18);
Veres et al. 2019 (RNA: hESC-derived MPCs);
Jiang et al. 2021 (RNA: hPSC-derived MPCs);
Olaniru et al. 2023 (RNA: GW8 of human embryonal pancreas); | No | Yes |
| PTF1A (RNA) | Cebola et al. 2015 (RNA: in vivo MPCs from human embryonic pancreas at CS16-18);
Veres et al. 2019 (RNA: hESC-derived MPCs); | No | Yes |
| SOX9 (protein, RNA) | Johannesson et al. 2009 (protein, RNA: hESC-derived MPCs);
Xu et al. 2011 (protein, RNA: hESC-derived MPCs);
Jennings et al. 2013 (protein: pancreatic bud cells at CS13);
Cebola et al. 2015 (RNA: in vivo MPCs from human embryonic pancreas at CS16-18);
Veres et al. 2019 (RNA: hESC-derived MPCs);
Jiang et al. 2021 (RNA: hPSC-derived MPCs);
Olaniru et al. 2023 (RNA: GW8 of human embryonal pancreas); | No | No |
FOXA2 (Forkhead Box A2), expressed from the definitive endoderm cell stage, continues to be expressed in the primary MPCs as the pancreas begins to form (Johannesson et al. 2009; Xu et al. 2011; Jennings et al. 2013; Cebola et al. 2015). Similarly, GATA4, also expressed at earlier developmental stages, continues to be expressed in primary MPCs (Jennings et al. 2013; Veres et al. 2019; Jiang et al. 2021).
GATA6 plays a crucial role in generation of MPCs and pancreatic agenesis results from GATA6 haploinsufficiency in humans (Allen et al. 2011), and homozygous Gata6 deletion in mice (Xuan et al. 2012). Similarly, PDX1 (Pancreatic and Duodenal Homeobox 1) is a transcription factor critical for pancreatic development and one of the earliest markers of MPCs, whose loss-of-function mutations lead to pancreatic insufficiency, including pancreatic agenesis (reviewed in Ebrahim et al. 2022). P2RY1 can be used as a surrogate surface marker for PDX1 (Qadir et al. 2018). ONECUT1 (HNF6), shown in mice to directly stimulate Pdx1 transcription (Jacquemin et al. 2023), is a crucial regulator of MPC development, with ONECUT1 loss-of-function mutation being an underlying cause of pancreatic hypoplasia and early-onset diabetes (Philippi et al. 2021). In Onecut1 knockout mice, the onset of Pdx1 expression in the foregut endoderm is delayed (Jacquemin et al. 2003). Onecut1 was implicated in the regulation of Foxa2 expression in mice (Rausa et al. 1998). PTF1A transcription factor is necessary for the control of expansion of MPCs and loss-of-function mutations in PTF1A lead to pancreatic and cerebellar agenesis (reviewed in Jin and Xiang 2019). Co-expression of PTF1A and PDX1 has been used in vivo and in vitro studies to mark the achievement of a pancreatic commitment state (Willet et al. 2014). SOX9 (SRY-Box Transcription Factor 9) is a transcription factor involved in maintaining progenitor cell identity (reviewed in Seymour 2014). SOX9 haploinsufficiency is the cause of campomelic dysplasia, a lethal autosomal dominant syndrome that mainly affects the skeleton, but can include pancreas dysmorphogenesis (reviewed in Seymour 2014).
HNF1B (Hepatocyte Nuclear Factor 1 Beta) is a transcription factor whose heterozygous loss-of-function mutations result in a multisystem disorder MODY5 which includes pancreatic hypoplasia and diabetes mellitus (reviewed in Bockenhauer and Jaureguiberry 2016). In hiPSCs, lack of HNF1B blocks specification of pancreatic fate from the foregut progenitor stage, but HNF1B haploinsufficiency allows differentiation of MPCs and insulin-secreting β-like cells (El-Khairi et al. 2021).
While NKX2-1 (also known as TTF1) is a marker of mouse MPCs, it is not expressed in human MPCs, which, instead, express a related transcription factor NKX6-1, not expressed in mouse MPCs (Jennings et al. 2013).
The effector of Hippo signaling TEAD1 and its coactivator YAP, were reported to directly regulate the enhancer network of many marker genes of MPCs (Cebola et al. 2015).
Growth factors that promote generation and expansion of MPCs are FGF7 (Ye et al. 2005; Mfopou et al. 2010; Dettmer et al. 2020) and FGF10 (Ye et al. 2005; Mfopou et al. 2010; Nostro et al. 2015; Bonfanti et al. 2015; Memon et al. 2018; Dettmer et al. 2020), secreted by the pancreatic embryonic mesenchyme, as well as EGF (Nostro et al. 2015; Bonfanti et al. 2015; Dettmer et al. 2020). FGF2 and FGF17 have an anti-pancreatic effect and suppress generation of MPCs (Dettmer et al. 2020).
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