From “ES-like” cells to induced pluripotent stem cells: A historical perspective in domestic animalsby Sehwon Koh, Jorge A. Piedrahita



Equine / Food Animals / Small Animals / Animal Science and Zoology


Lens Differentiation from Embryonic Stem (ES) and Induced Pluripotent Stem (iPS) Cells

Ales Cvekl, Ying Yang, Yang Jing, Qing Xie

Induced Pluripotent Stem Cells

Keisuke Okita, Shinya Yamanaka

Production of Embryonic and Fetal-Like Red Blood Cells from Human Induced Pluripotent Stem Cells

Chan-Jung Chang, Koyel Mitra, Mariko Koya, Michelle Velho, Romain Desprat, Jack Lenz, Eric E. Bouhassira

Cdx2 Efficiently Induces Trophoblast Stem-Like Cells in Naïve, but Not Primed, Pluripotent Stem Cells

Stephanie Blij, Anthony Parenti, Neeloufar Tabatabai-Yazdi, Amy Ralston


rip a State e, No , USA

Received 7 August 2013

Received in revised form 5 September 2013

Accepted 5 September 2013


Pluripotent stem cells or cell lines derived from genital ridges of developing fetuses characteristics with ESCs in morphology, self-renewal, and differentiation potency [3]. Their theoretical advantage is that they can be generated from essentially any starting cell type and reintroduced into the donor allowing autologous transplantation without the practical or ethical concerns of

ESCs and EpiSCs. * Corresponding author. Tel.: þ1 9195157407; fax: þ1 9195137301.

E-mail address: (J.A. Piedrahita). 1 Current affiliation: Department of Cell Biology, Duke University,

Durham, North Carolina, USA

Contents lists available at ScienceDirect

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Theriogenology 81 (2014) 103–1111. Introduction

Stem cells are characterized by their self-renewal capacity and the potential to differentiate into different cell types, and are generally categorized depending on the range of different cell types they can generate. Stem cells can range fromunipotent stem cells, such asmuscle progenitor cells [1] to multipotent or pluripotent stem cells. Although pluripotent stem cells are able to differentiate into multiple tissues of all three germ layers, multipotent stem cells have more restricted differentiation potential [2]. Pluripotent stem cells includes cell lines isolated from developing embryos such as embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs), (embryonic germ cells). Embryonic stem cells are isolated from inner cell mass of pre-implantation stage embryo, whereas EpiSCs are derived from post-implantation stage embryos. Multipotent stem cells are isolated from adult tissues and include stem cells such as bone marrow-derived mesenchymal stem cell, and adipose-derived mesenchymal stem cells. Although more restrictive in their ability to differentiate, they are easily collected and expanded, allowing autologous transplantation, something that is much more difficult to do with ESCs and EpiSCs. More recently, induced pluripotent stem cells (iPSCs) were generated by ectopic expression of various defined transcription factors in somatic cells and these cells were shown to have similarReprogramming

Large animals

Induced pluripotent stem cells0093-691X/$ – see front matter  2014 Elsevier Inc (iPSCs) provide great potential as cell sources for gene editing to generate genetically modified animals, as well as in the field of regenerative medicine. Stable, long-term ESCs have been established in laboratory mouse and rat; however, isolation of true pluripotent

ESCs in domesticated animals such as pigs and dogs have been less successful. Initially, domesticated animal pluripotent cell lines were referred to as “embryonic stem-like” cells owing to their similar morphologic characteristics to mouse ESCs, but accompanied by a limited ability to proliferate in vitro in an undifferentiated state. That is, they shared some but not all the characteristics of true ESCs. More recently, advances in reprogramming using exogenous transcription factors, combined with the utilization of small chemical inhibitors of key biochemical pathways, have led to the isolation of iPSCs. In this review, we provide a historical perspective of the isolation of various types of pluripotent stem cells in domesticated animals. In addition, we summarize the latest progress and limitations in the derivation and application of iPSCs.  2014 Elsevier Inc. All rights reserved.Article history: Pluripotent stem cells such as embryonic stem cells (ESCs) and induced pluripotent stema r t i c l e i n f o a b s t r a c t40th Anniversary Special Issue

From “ES-like” cells to induced plu perspective in domestic animals

Sehwon Koh a,c,1, Jorge A. Piedrahita a,b,c,* aCenter for Comparative Medicine and Translational Research, North Carolin bDepartment of Molecular Biomedical Sciences, College of Veterinary Medicin cGenomics Program, North Carolina State University, Raleigh, North Carolina. All rights reserved. 09otent stem cells: A historical

University, Raleigh, North Carolina, USA rth Carolina State University, Raleigh, North Carolina, USA ology . ther io journal .com

S. Koh, J.A. Piedrahita / Theriogenology 81 (2014) 103–1111042. Historical perspectives

Work related to identification of pluripotent stem cells in species other than mice was driven initially by the observations of Bradley, et al. [4] that mouse ESCs could contribute to the formation of the whole organism, including the germline, when injected into the developing blastocysts. This was quickly followed by the demonstration that ESCs could be genetically manipulated in vitro and used to generate germline chimeras that could transmit the genetic modification to the next generation, thus allowing the establishment of transgenic mouse lines [5–8]. This led to the work of Smithies, et al. [9,10], showing for the first time that specific genes could be modified by a technique known as homologous recombination. This work eventually led to the Nobel Prize in Medicine in 2007 [11]. More recently, ESCs have been subcategorized into “true” ESCs and EpiSCs, and into naïve and primed ESCs, respectively [12–14], with only naïve, pluripotent cells being able to contribute to chimeric offspring.

For those of us following the early work, it was obvious that the embryonic stem (ES)-based approach would have many applications in domestic animals and many of us embarked in a rather frustrating journey attempting to isolate and characterize ES and embryonic germ cells from a range of domestic animals [reviewed in 15–18]. However, although the field has progressed over the last 30 years, we still do not have ESCs in any domestic species that can be consideredpractical for the generation of transgenic animals.

Domesticated animals such as dogs, pigs, and cows are considered excellent models for long-term experiments in regenerative medicines, and biomedical research in general, because of their similarities in physiology with humans compared with the laboratory mouse or rat [19– 21]. Furthermore, mice with targeted gene manipulation in most cases failed to reproduce typical human phenotypes [8,22–24]. As a result, derivation of stem cell lines from large animals such as dogs, pigs, cattle, goats, and horses has been of great interest because it benefits both clinical applications to improve human health and agricultural applications. Although there have been many reports of isolated stem cell lines, all of them without exception lack either convincing proof of pluripotency or require such demanding methods for establishment and maintenance that they are, for all intents and purposes, impractical (see [15–18] for details).