The novel tool of cell reprogramming for applications in molecular medicine

Journal of Molecular Medicine, Jun 2017

Recent discoveries in the field of stem cell biology have enabled scientists to “reprogram” cells from one type to another. For example, it is now possible to place adult skin or blood cells in a dish and convert them into neurons, liver, or heart cells. It is also possible to literally “rejuvenate” adult cells by reprogramming them into embryonic-like stem cells, which in turn can be differentiated into every tissue and cell type of the human body. Our ability to reprogram cell types has four main implications for medicine: (1) scientists can now take skin or blood cells from patients and convert them to other cells to study disease processes. This disease modeling approach has the advantage over animal models because it is directly based on human patient cells. (2) Reprogramming could also be used as a “clinical trial in a dish” to evaluate the general efficacy and safety of newly developed drugs on human patient cells before they would be tested in animal models or people. (3) In addition, many drugs have deleterious side effects like heart arrhythmias in only a small and unpredictable subpopulation of patients. Reprogramming could facilitate precision medicine by testing the safety of already approved drugs first on reprogrammed patient cells in a personalized manner prior to administration. For example, drugs known to sometimes cause arrhythmias could be first tested on reprogrammed heart cells from individual patients. (4) Finally, reprogramming allows the generation of new tissues that could be grafted therapeutically to regenerate lost or damaged cells.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://link.springer.com/content/pdf/10.1007%2Fs00109-017-1550-4.pdf

The novel tool of cell reprogramming for applications in molecular medicine

The novel tool of cell reprogramming for applications in molecular medicine Moritz Mall 0 Marius Wernig 0 0 Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine , Stanford, CA 94305 , USA Recent discoveries in the field of stem cell biology have enabled scientists to Breprogram^ cells from one type to another. For example, it is now possible to place adult skin or blood cells in a dish and convert them into neurons, liver, or heart cells. It is also possible to literally Brejuvenate^ adult cells by reprogramming them into embryonic-like stem cells, which in turn can be differentiated into every tissue and cell type of the human body. Our ability to reprogram cell types has four main implications for medicine: (1) scientists can now take skin or blood cells from patients and convert them to other cells to study disease processes. This disease modeling approach has the advantage over animal models because it is directly based on human patient cells. (2) Reprogramming could also be used as a Bclinical trial in a dish^ to evaluate the general efficacy and safety of newly developed drugs on human patient cells before they would be tested in animal models or people. (3) In addition, many drugs have deleterious side effects like heart arrhythmias in only a small and unpredictable subpopulation of patients. Reprogramming could facilitate precision medicine by testing the safety of already approved drugs first on reprogrammed patient cells in a personalized manner prior to administration. For example, drugs known to sometimes cause arrhythmias could be first tested on reprogrammed heart cells from individual patients. (4) Finally, reprogramming allows the generation of new tissues that could be grafted therapeutically to regenerate lost or damaged cells. Cell fate; Reprogramming; Stem cell biology - The fate of a cell is an integral of its morphological and functional makeup that is in turn dictated by its transcriptional, epigenetic, proteomic, and metabolic configuration. Cellular fate is changing during development as the multicellular organism develops from a single totipotent cell to yield billions of specialized cells that make up the human body. Ever since Hans Spemann showed in 1923 that the blastomeres of a 16cell salamander embryo are all equivalent to the totipotent zygote, it remained an open question whether more differentiated cells irreversibly lose this developmental potential [1]. It was debated whether perhaps even genetic material might be lost during differentiation, which would eliminate the totipotent potential of specialized cells. One of the first decisive experiments was the nuclear transfer of specialized cell nuclei into oocytes (Fig. 1a). These experiments first done in frogs showed that specialized cells can be reprogrammed to totipotency and can give rise to a new animal [2, 3]. Thus, even specialized cells can activate the entire program of embryonic development. In addition, adult cells can adapt and change quite dramatically upon certain environmental conditions. For example, the respiratory epithelium in the lungs of smokers can convert into squamous cells, and the esophagus epithelium can adopt the morphology of gastric epithelium in a process called metaplasia [4]. But also in hematopoietic tumors, cells have been found to transdifferentiate from one blood lineage to another [5, 6]. There is also evidence that pancreatic α or δ cells can change to β cells upon injury [7, 8]. An additional example for induced lineage plasticity was provided by cell fusion experiments (Fig. 1b) [9, 10]. transfer somatic nucleus into enucleated oocyte heterokaryon expressing human muslce genes transcription factor-mediated reprogramming (OSKM) Fig. 1 Common technologies to reprogram cell fate. a Somatic cell nuclear transfer (SCNT), in which an oocyte is enucleated to receive a nucleus from a donor cell such as a fibroblast uses the cytoplasmic machinery to reprogram the donor cell to pluripotency. Similar methods were used to clone entire animals such as Dolly the sheep and generate human stem cell lines. b Analogous to SCNT diffusible factors can reprogram the expression program of a donor cell such as a human amniocyte upon induced cell fusion with heterologous cells such as mouse myocytes to induce the expression of human muscle genes. c Alternatively, strong cell fate determination transcription factors can be overexpressed using different methods to change a cell fate. For example, the transcription factors Oct4, Sox2, Klf4, and c-Myc (OSKM) can convert a fibroblast into an induced pluripotent stem cell More recently, specific transcription factors or combinations thereof have been identified to induce such lineage conversions (Fig. 1c). Among others, MyoD was found to induce muscle fates in fibroblasts [11], Pax6 was shown to induce entire ectopic eyes [12], and several factors in combination could induce insulin (...truncated)


This is a preview of a remote PDF: https://link.springer.com/content/pdf/10.1007%2Fs00109-017-1550-4.pdf

Moritz Mall, Marius Wernig. The novel tool of cell reprogramming for applications in molecular medicine, Journal of Molecular Medicine, 2017, pp. 695-703, Volume 95, Issue 7, DOI: 10.1007/s00109-017-1550-4