Weizmann scientists make stem cell reprogramming easier

New research find "brake" holding back production of stem cells and release it to synchronize process, increase efficiency.

By JUDY SIEGEL-ITZKOVICH
Stem Cells 311 (photo credit: (University of Louisville Medical School)
Stem Cells 311
(photo credit: (University of Louisville Medical School)
Weizmann Institute scientists have streamlined the painstaking process of turning the clock back on adult cells in the human body and changing them into embryonic-like stem cells to replace sick cells, according to a study just published in the prestigious journal Nature.
Embryonic stem cells have the potential to treat and cure many medical problems.
That is why the discovery that induced-embryonic-like stem cells can be created from skin cells (iPS cells) was rewarded with a Nobel Prize in 2012.
Scientists have been removing one protein from adult cells to turn them into a stem-cell-like state. But the process has remained frustratingly slow and inefficient, and the resulting stem cells are not yet ready for medical use.
The new research in the Rehovot lab of Dr. Yaqub Hanna dramatically changes that. He and his colleagues revealed the “brakes” holding back the production of stem cells and found that releasing this brake can synchronize the process and increase its efficiency from around 1 percent or less today to 100%.
They say their findings may help facilitate the production of stem cells for medical use, as well as advance our understanding of the mysterious process by which adult cells can revert back into their original, embryonic state.
Embryonic stem cells are those that have not undergone any “specialization” so they can give rise to any type of cell in the body. This is what makes them so valuable.
They can be used, among other things, to repair damaged tissue, treat autoimmune disease and even grow transplant organs.
Using stem cells taken from embryos is difficult because of there are not large supplies and because of ethical concerns (although Jewish law is liberal on using unimplanted embryos for medical research that would benefit mankind, so Israeli researchers do not face the limitations in other countries).
The hopes for their use were renewed in 2006, when a team led by Shinya Yamanaka of Kyoto University discovered it is possible to “reprogram” adult cells.
The resulting cells, called “induced pluripotent stem cells (iPSCs), are created by inserting four genes into their DNA. Despite this breakthrough, the reprograming process is very difficult: It can take up to a month; the timing is not coordinated among the cells; and less than 1% of the treated cells end up becoming stem cells.
Hanna and his team wondered what the main obstacle was that prevents successful reprograming in the majority of cells. In his postdoctoral research, Hanna had employed mathematical models to show that a single obstacle was responsible. Of course in biology, Hanna is the first to admit, experimental proof is required to back up the models. The present study not only provides the proof, it identifies that single obstacle and shows that removing it can dramatically improve reprograming.
Hanna’s group, led by Dr. Noa Novershtern, Yoach Rais, Asaf Zviran and Shay Geula of the molecular genetics department, together with members of the genomics unit of the Weizmann Institute’s Israel Structural Proteomics Center, studied a protein called MBD3, whose function was unknown. MBD3 had caught their attention because – unusually – it is expressed in every cell in the body, at every stage of development.
Most proteins are produced in specific cells, at specific times, for specific functions.
The team found that there is one exception to the rule of universal expression of this protein – the first three days after conception. These are exactly the three days in which the fertilized egg begins dividing, and the nascent embryo is a growing ball of pluripotent stem cells that will eventually supply all the cell types in the body.
Starting on the fourth day, differentiation begins and the cells start to lose their pluripotent status. And that is just when the MBD3 proteins first appear.
This finding has significant implications for the producing iPSCs for medical use. Yamanaka used viruses to insert the four genes but, for safety reasons, these are not used in reprograming cells to be used in patients.
This gives the process an even lower success rate of only around a 10th of a percent.
The Weizmann researchers showed that removing MBD3 from the adult cells can improve efficiency and speed the process by orders of magnitude. The time needed to produce the stem cells was shortened from four weeks to eight days. As a bonus, since the cells all underwent the reprograming at the same rate, the scientists will now be able, for the first time, to follow it step by step and reveal its mechanisms of operation.
Hanna points out that his team’s achievement was based on research into the natural pathways of embryonic development. Scientists investigating reprograming, he concludes, can benefit from a deeper understanding of how embryonic stem cells are produced in nature.
“After all, nature still makes them best, in the most efficient manner.”