Transdifferentiation and reprogramming: Overview of the processes, their similarities and differences

Abstract

Reprogramming, or generation of induced pluripotent stem (iPS) cells (functionally similar to embryonic stem cells or ES cells) by the use of transcription factors (typically: Oct3/4, Sox2, c-Myc, Klf4) called "Yamanaka factors" (OSKM), has revolutionized regenerative medicine. However, factors used to induce stemness are also overexpressed in cancer. Both, ES cells and iPS cells cause teratoma formation when injected to tissues. This raises a safety concern for therapies based on iPS derivates. Transdifferentiation (lineage reprogramming, or -conversion), is a process in which one mature, specialized cell type changes into another without entering a pluripotent state. This process involves an ectopic expression of transcription factors and/or other stimuli. Unlike in the case of reprogramming, tissues obtained by this method do not carry the risk of subsequent teratomagenesis.

Neurothreads: Cryogel carrier-based differentiation and delivery of mature neurons in the treatment of Parkinson’s disease

“…Our results highlight the need for tight control of proliferation and terminal differentiation. This underscores the importance of emerging approaches such as the incorporation of a suicide gene for proliferating cells into the graft 86 , selection of a suitable progenitor population, expressing specific surface ventral midbrain markers 88 , or by trans-differentiation of more mature cells 89 . It also underpins the importance of approaches such as the one investigated here that enable prolonged maturation prior to implantation, offering the possibility of later quality control points.…”

Regulation of blood cell transdifferentiation by oxygen sensing neurons

“…Transdifferentiation is known in many species including vertebrates (Cieslar-Pobuda et al, 2017;Reid and Tursun, 2018), but in the blood cell system transdifferentiation has for the most part only been studied in vitro and by experimental manipulations. For example, C/EBP (CCAAT/enhancerbinding protein) transcription factors drive transdifferentiation of vertebrate B cells into macrophages (Xie et al, 2004) (Di Tullio et al, 2011), force B lymphoma and leukemia cell lines to transdifferentiate into macrophages (Rapino et al, 2013), and facilitate B cell transdifferentiation to Granulocyte-Macrophage Precursors (Cirovic et al, 2017).…”

Take the shortcut – direct conversion of somatic cells into induced neural stem cells and their biomedical applications

“…In contrast to previous observations, Bar-nur et al [43] surprisingly showed that BSKM was actually able to generate iPSC-like colonies and hallmarked by activation of endogenous pluripotency genes Oct4, Nanog, and Zfp42, in both embryonic stem cell and NSC media. In conclusion, identification of potential pluripotency intermediates during reprogramming procedures is important to distinguish between iPSC-coupled mechanisms and true transdifferentiation [40,43,44]. Another study used two lineage tracing systems, Nanog-CreER and Oct4-CreER, to follow the transdifferentiation of mouse embryonic fibroblasts (MEFs) toward cardiomyocytes or iNSCs [44].…”

“…Induced neural stem cells are generated through direct conversion, a process in which cells acquire the expression of NSC markers in a stepwise fashion, theoretically without passing through a pluripotent state [40]. However, most protocols for iNSC generation involve the Yamanaka factors OSKM [11,13,25,26,41,42], suggesting that cells undergo a transient pluripotent state during the reprogramming process.…”

“…Notably, the authors stated that transduction of Oct4 protein or mRNA transfection is preferable to transcriptional control. In conclusion, identification of potential pluripotency intermediates during reprogramming procedures is important to distinguish between iPSC-coupled mechanisms and true transdifferentiation [40,43,44].…”