Derivation of elephant induced pluripotent stem cells

Abstract

The crisis of biodiversity loss in the anthropogenic era requires new tools for studying non-model organisms. Elephants, for example, are both an endangered species and excellent models studying complex phenotypes like size, social behavior, and longevity, but they remain severely understudied. Here we report the first derivation of elephant (Elephas maximus) induced pluripotent stem cells (emiPSCs) achieved via a two-step process of chemical-media induction and colony selection, followed by overexpression of elephant transcription factors OCT4, SOX2, KLF4, MYC +/- NANOG and LIN28A, and modulation of the TP53 pathway. Since the seminal discovery of reprogramming by Shinya Yamanaka, iPSCs from many species including the functionally extinct northern white rhinocerous have been reported, but emiPSCs have remained elusive. While for multiple species the reprogramming protocol was adopted with little changes compared to model organisms like mouse and human, our emiPSC protocol requires a longer timeline and inhibition of TP53 expansion genes that are hypothesized to confer unique cancer resistance in elephants. iPSCs unlock tremendous potential to explore cell fate determination, cell and tissue development, cell therapies, drug screening, disease modeling, cancer development, gametogenesis and beyond to further our understanding of this iconic megafauna. This study opens new frontiers in advanced non-model organism cellular models for genetic rescue and conservation.

Pervasive loss of regulated necrotic cell death genes in elephants, hyraxes, and sea cows (Paenungualta)

“…Elephants have evolved remarkably large body sizes and a low prevalence of cancer (Abegglen et al, 2015; Bulls et al, 2022; Compton et al, 2023; Tollis et al, 2021). Among the anti–cancer cellular phenotypes in elephants are cells that induce apoptosis at low levels of DNA damage (Abegglen et al, 2015; Sulak et al, 2016a; Vazquez et al, 2018), are resistant to oxidative stress-induced cell death (Gomes et al, 2011), have faster DNA damage repair rates than smaller-bodied species (Francis et al, 1981; Hart and Setlow, 1974; Promislow, 1994), are resistant to experimental immortalization (Fukuda et al, 2016; Gomes et al, 2011), and that may have a genetic and/or epigenetic barrier to experimental induction of pluripotency (Appleton et al, 2024). These cellular traits are at least partly mediated by an increase in the number of tumor suppressors in the elephant lineage (Caulin et al, 2015; Doherty and Magalhães, 2016; Sulak et al, 2016b; Tollis et al, 2020; Vazquez et al, 2018; Vazquez and Lynch, 2021).…”