The primary multipotent pancreatic progenitor cells (MPCs) are initially undifferentiated and can give rise to both tip and trunk cells (reviewed in Jennings et al. 2015). As development progresses, at Carnegie stage CS19 (45-47 days post-conception, corresponding to post-conception week PCW7 or gestation week GW9) in humans, GATA4 becomes restricted to peripheral, tip MPCs (Jennings et al. 2013), located at the ends (tips) of the growing branches of the pancreatic epithelium (reviewed in Jennings et al. 2015). Branching morphogenesis of pancreas does not follow the stereotypical branching pattern where branches grow by splitting of an initial stem (reviewed in Flasse et al. 2021). Instead, a microlumen is formed in a mass of MPCs and nearby microlumen fuse and progressively connect into a tree through stochastic tubulogenesis, with tip cells lining the central lumen which will become acini, while the trunk cells line the tubules that will eventually become ducts (reviewed in Flasse et al. 2021). CDC42 is essential for initiating microlumen formation and initial tubulogenesis, as well as for the establishment of tip-trunk polarity (Kesavan et al. 2009). Tip multipotent pancreatic progenitor cells continue to proliferate and initially maintain their multipotent state but become increasingly committed to the exocrine fate (Villani et al. 2019).
Tip progenitors are MPC-like and their markers tested so far largely overlap with MPC markers:
PTF1A is highly expressed in tip progenitor cells at mRNA and protein levels and is necessary for their commitment to the acinar lineage (Villani et al. 2019, Olaniru et al. 2019). Expression of RBPJL, cofactor of PTF1A involved in the transcriptional regulation of genes specific to the acinar lineage, in tip progenitor cells at the RNA level (Olaniru et al. 2023) marks their differentiation toward the acinar cell fate. The switch, at the protein level, from RBPJ to RBPJL within the PTF1 complex (complex of PTF1A and RBPJ or RBPJL) is essential for the final step of acinar cell maturation (Masui et al. 2010) and is facilitated by the nuclear hormone receptor NR5A2 (Hale et al. 2014).
Jennings, RE, Berry, AA, Kirkwood-Wilson, R, Roberts, NA, Hearn, T, Salisbury, RJ, Blaylock, J, Piper Hanley, K, Hanley, NA
Olaniru, OE, Kadolsky, U, Kannambath, S, Vaikkinen, H, Fung, K, Dhami, P, Persaud, SJ
Villani, V, Thornton, ME, Zook, HN, Crook, CJ, Grubbs, BH, Orlando, G, De Filippo, R, Ku, HT, Perin, L
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