OCT4 induces long-lived dedifferentiated kidney progenitors poised to redifferentiate in 3D kidney spheroids

Dorit Omer, Osnat Cohen Zontag, Yehudit Gnatek, Orit Harari-Steinberg, Oren Pleniceanu, Michael Namestnikov, Ayelet Hashahar Cohen, Malka Nissim-Rafinia, Gal Tam, Tomer Kalisky, Eran Meshorer, Benjamin Dekel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Upscaling of kidney epithelial cells is crucial for renal regenerative medicine. Nonetheless, the adult kidney lacks a distinct stem cell hierarchy, limiting the ability to long-term propagate clonal populations of primary cells that retain renal identity. Toward this goal, we tested the paradigm of shifting the balance between differentiation and stemness in the kidney by introducing a single pluripotency factor, OCT4. Here we show that ectopic expression of OCT4 in human adult kidney epithelial cells (hKEpC) induces the cells to dedifferentiate, stably proliferate, and clonally emerge over many generations. Control hKEpC dedifferentiate, assume fibroblastic morphology, and completely lose clonogenic capacity. Analysis of gene expression and histone methylation patterns revealed that OCT4 represses the HNF1B gene module, which is critical for kidney epithelial differentiation, and concomitantly activates stemness-related pathways. OCT4-hKEpC can be long-term expanded in the dedifferentiated state that is primed for renal differentiation. Thus, when expanded OCT4-hKEpC are grown as kidney spheroids (OCT4-kSPH), they reactivate the HNF1B gene signature, redifferentiate, and efficiently generate renal structures in vivo. Hence, changes occurring in the cellular state of hKEpC following OCT4 induction, long-term propagation, and 3D aggregation afford rapid scale-up technology of primary renal tissue-forming cells.

Original languageAmerican English
Pages (from-to)329-346
Number of pages18
JournalMolecular Therapy Methods and Clinical Development
Volume29
DOIs
StatePublished - 8 Jun 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Keywords

  • CKD
  • cell therapy
  • chronic kidney disease
  • dedifferentiation
  • kidney organoid
  • kidney progenitor
  • kidney regeneration
  • kidney spheroid
  • long-term expansion
  • redifferentiation
  • reprogramming
  • tubuloid

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