Spatiotemporal reprogramming of differentiated cells underlies regeneration and neoplasia in the intestinal epithelium

Abstract

Although the mammalian intestinal epithelium manifests robust regenerative capacity after various cytotoxic injuries, the underlying mechanism has remained unclear. Here we identify the cyclin-dependent kinase inhibitor p57 as a specific marker for a quiescent cell population located around the +4 position of intestinal crypts. Lineage tracing reveals that the p57+ cells serve as enteroendocrine/tuft cell precursors under normal conditions but dedifferentiate and act as facultative stem cells to support regeneration after injury. Single-cell transcriptomics analysis shows that the p57+ cells undergo a dynamic reprogramming process after injury that is characterized by fetal-like conversion and metaplasia-like transformation. Population-level analysis also detects such spatiotemporal reprogramming widely in other differentiated cell types. In intestinal adenoma, p57+ cells manifest homeostatic stem cell activity, in the context of constitutively activated spatiotemporal reprogramming. Our results highlight a pronounced plasticity of the intestinal epithelium that supports maintenance of tissue integrity in normal and neoplastic contexts.

p57Kip2 acts as a transcriptional corepressor to regulate intestinal stem cell fate and proliferation

“…Consistent with p57 immunostaining (Figure 1G and S1B) showing no signal in lower crypts, p57 was expressed at low levels in Lgr5 + ISCs (GFP High ) and TA cells (GFP Low ) but was abundant in differentiated (GFP Neg ) cells (Figure 4A). In contrast, p57 mRNA expression was high in Hopx-GFP + cells (Figure 4B), in agreement with the reported expression of p57 in quiescent Mex3a High or Bmi1 High ISCs [11, 12]. To confirm the expression of p57 in +4 reserve ISCs, p57 expression was investigated by immunostaining in E18.5 intestines from p57 +/+ ;Hopx +/3xFlag-eGFP .…”

“…Disruption of Notch1 and -2 results in derepression of p27 and p57 and in premature cell cycle exit and differentiation of intestinal progenitors [10]. More recently, p57 expression was detected in populations of quiescent Mex3a High and Bmi1 High ISCs, but its mechanism of action has not been studied [11, 12].…”

Applications of human organoids in the personalized treatment for digestive diseases

“…For example, p57 + cells exhibit quiescent stem cell activity, undergoing a dynamic reprogramming process of differentiation as part of constitutively activated spatiotemporal reprogramming and as facultative stem cells, supporting regeneration after injury. 374 Single-cell sequencing of highly proliferating intestinal organoids obtained using a combination of chemicals and factors revealed variable expression of regenerative stem cells, such as in vivo damage-responsive Clu + revival stem cells or Lgr5 + stem cells for tissue repair through epigenetic reprogramming. 350 The theory of dedifferentiation suggests that epithelial cells are uniquely plastic, enabling them to dedifferentiate and replenish the pool of cycling cells lost upon damage; thus, by reverting to a more primitive state, the organ allows itself to remodel tissue patterns into homeostatic tissue compartments and induce regeneration.…”

Challenges and opportunities targeting mechanisms of epithelial injury and recovery in acute intestinal graft-versus-host disease

“…Upon CBC ablation, progenitors were able to dedifferentiate and regain stemness, thereby replenishing the ISC pool and subsequently the mature enterocytes at the epithelial surface 120 . Both secretory 121 , 122 and enterocyte 123 progenitors are capable of this reversion, and even fully differentiated enterocytes can contribute to crypt repopulation under specific circumstances of extreme damage 124 . In both instances, the expression of Lgr5 reappeared at the base of the crypt 121 , 123 , preceded by the re-expression of the ISC-restricted transcription factor Ascl2 125 .…”

“…Even a subset of Paneth cells acquired multipotency upon irradiation through Notch activation 126 . The reprogramming of adult differentiated cells appears to have a developmental link 122 , as fetal mouse IECs can give rise to the adult ISC pool irrespective of their location or Lgr5 status 127 . Additionally, during infectious insult fetal-type gene expression programs play a role in epithelial recovery, as the murine ISC niche can revert to a fetal-like state upon parasitic helminth infection 128 .…”