Reprogramming Adult Patient Cells into Stem Cells: the Promise of Personalized Genetic Therapy

Reprogramming Adult Patient Cells into Stem Cells: the Promise of Personalized Genetic Therapy

Reporter: Aviva Lev-Ari, PhD, RN


Major breakthrough in understanding a parental imprinting disorder is achieved by researchers at the Hebrew University

Modeling Prader-Willi syndrome in stem cells published in Nature Genetics

Scientists at the Hebrew University of Jerusalem have reported a major breakthrough in understanding the molecular basis for Prader-Willi syndrome (PWS), perhaps the most studied among the class of diseases that involves defects in parental imprinting.

The work, described in the latest online edition of the prestigious journal Nature Genetics, was led by Prof. Nissim Benvenisty, the Herbert Cohn Professor of Cancer Research and director of the Stem Cell Unit at the Alexander Silberman Institute of Life Sciences at the Hebrew University; and his PhD student Yonatan Stelzer. Also assisting in the research were graduate student Ido Sagi and Dr. Ofra Yanuka and Dr. Rachel Eiges.

Parental imprinting is a mode of inheritance that results in a small subset of genes to be expressed exclusively from either the mother or father. Prader-Willi syndrome is perhaps the best characterized disease of this sort. It is a multisystem disorder characterized by learning disabilities, excessive weight gain and defective sexual development, and is known to result from aberrations in paternal genes in what is known as the Prader-Willi genomic region of chromosome 15.

“What characterizes this chromosomal region is that paternal genes are active, while the maternal genes are inactive. And while most people would have one normal working and one silenced set of these genes, people with Prader-Willi syndrome have only a defective set (the paternal one) and a silenced (maternal) set,” explains Stelzer.

In order to achieve a greater understanding of this process, the Hebrew University investigators created a model for the Prader-Willi syndrome by reprogramming skin cells from PWS patients into embryonic-like cells. Utilizing this system, the investigators have shown that the genes expressed from the father are actually affecting and silencing the genes that are expressed from the mother. These findings have significance in the way that we view parental imprinting and in particular the molecular basis of Prader-Willi syndrome, the scientists say.

Future research should allow further characterization of the contribution of this novel genetic region to the origin of this disease, and perhaps pave the way for identification of possible treatment and characterization of PWS patients. Furthermore, the identification of functional, genomic cross-talk in regions containing parental imprinted genes may significantly change our overall understanding of the evolution of this phenomenon in placental mammals, say the researchers.

The research study, “The noncoding RNA IPW regulates the imprintedDLK1DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome,” was partially funded by the Israel Science Foundation–Morasha Foundation and by the Israel Ministry of Science and Technology Infrastructure.




  1. Stem Cell Unit, Department of Genetics, Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.

    • Yonatan Stelzer,
    • Ido Sagi,
    • Ofra Yanuka &
    • Nissim Benvenisty
  2. Stem Cell Research Laboratory, Shaare Zedek Medical Center, The Hebrew University, Jerusalem, Israel.

    • Rachel Eiges


Y.S. contributed to the conception and design of the study, the collection and assembly of data, data analysis and interpretation, and manuscript writing. I.S. contributed to the collection and assembly of data and graphic design. O.Y. and R.E. contributed to the collection and assembly of data. N.B. contributed to the conception and design of the study, financial support, data analysis and interpretation, and manuscript writing.

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

Received05 December 2013 
Accepted 03 April 2014 
Published online 11 May 2014

Parental imprinting is a form of epigenetic regulation that results in parent-of-origin differential gene expression. To study Prader-Willi syndrome (PWS), a developmental imprinting disorder, we generated case-derived induced pluripotent stem cells (iPSCs) harboring distinct aberrations in the affected region on chromosome 15. In studying PWS-iPSCs and human parthenogenetic iPSCs, we unexpectedly found substantial upregulation of virtually all maternally expressed genes (MEGs) in the imprinted DLK1DIO3 locus on chromosome 14. Subsequently, we determined that IPW, a long noncoding RNA in the critical region of the PWS locus, is a regulator of the DLK1DIO3 region, as its overexpression in PWS and parthenogenetic iPSCs resulted in downregulation of MEGs in this locus. We further show that gene expression changes in the DLK1DIO3 region coincide with chromatin modifications rather than DNA methylation levels. Our results suggest that a subset of PWS phenotypes may arise from dysregulation of an imprinted locus distinct from the PWS region.




  • reprogram adult patient cells into stem cells

    The capacity to reprogram adult patient cells into pluripotent, embryonic-like, stem cells by nuclear transfer has been reported as a breakthrough by scientists from the US and The Hebrew University of Jerusalem.

    The work, described in the journal Nature, was accomplished by researchers from the New York Stem Cell Foundation Research Institute and Columbia University and by Nissim Benvenisty, the Herbert Cohn Professor of Cancer Research and Director of the Stem Cell Unit at the Institute of Life Sciences at The Hebrew University of Jerusalem, and his graduate student Ido Sagi. The latter assisted in the characterization of the pluripotent nature of these cells.

    Pluripotency means the ability of stem cells to develop into all the cells of our body, including those in the brain, heart, liver and blood. In 2012, the Nobel Prize in Physiology or Medicine was awarded for two discoveries showing that mature (differentiated) cells can be converted into pluripotent, embryonic-like cells, either by forced expression of genetic factors or by transfer of cell nuclei into female eggs, in a process called “reprogramming.”

    However, the actual ability to reprogram cells from humans by nuclear transfer had only been accomplished until now by using fetal cells for this purpose, until this latest work involving reprogramming of adult patient cells demonstrated by the researchers from the US and The Hebrew University, as described in the new Nature article.

    Future research should allow further characterization of these novel, pluripotent cell types and their comparison to other stem cells. “Human pluripotent stem cells generated from adult cells may change the face of medicine,” says Professor Benvenisty, leading to totally new, personalized genetic therapy involving the reprograming of a patient’s own cells to achieve cell replacement and healing.

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