Outside-In Reprogramming: Antibody Study Suggests a Better Way to Make Stem Cells
September 11, 2017
LA JOLLA, CA Scientists at The Scripps Research Institute (TSRI) have found a new approach to the reprogramming of ordinary adult cells into stem cells.
In a study published today in an Advance Online paper in Nature Biotechnology, the TSRI scientists screened a library of 100 million antibodies and found several that can help reprogram mature skin-like cells into stem cells known as induced pluripotent stem cells (IPSCs).
Making IPSCs from more mature types of cells normally involves the insertions of four transcription factor genes into the DNA of those cells. The antibodies identified by the scientists can be applied to mature cells where they bind to proteins on the cell surface as a substitute for three of the standard transcription factor gene-insertions.
This result suggests that ultimately we might be able to make IPSCs without putting anything in the cell nucleus, which potentially means that these stem cells will have fewer mutations and overall better properties, said study senior author Kristin Baldwin, associate professor in TSRI's department of neuroscience.
IPSCs can be made from patients' own cells, and have a multitude of potential uses in personalized cell therapies and organ regeneration. However, none of IPSCs' envisioned clinical uses has yet been realized, in part because of the risks involved in making them.
The standard IPSC induction procedure, developed a decade ago and known as OSKM, involves the insertion into adult cells of genes for four transcription factor proteins: Oct4, Sox2, Klf4 and c-Myc. With these genes added and active, the transcription factor proteins they encode are produced and in turn reprogram the cells to become IPSCs.
One problem with this procedure is that the viral insertion events or overproduction of the nuclear reprogramming factors may damage cell DNA in a way that turns the cell cancerous. Another is that this nuclear reprogramming typically yields a collection of IPSCs with variable properties. This variability can be a problem even when we're using IPSCs in the laboratory for studying diseases, Baldwin said.
In contrast, during ordinary animal development, cell identity is altered by molecular signals that come in from outside the cell and induce changes in gene activity, without any risky insertions of DNA. To find natural pathways like these through which ordinary cells could be turned into IPSCs Baldwin and her laboratory teamed up with the TSRI laboratory of Richard Lerner, the Lita Annenberg Hazen Professor of Immunochemistry. Lerner has helped pioneer the development and screening of large libraries of human antibodies for finding new antibody-based drugs and scientific probes.
In this case, the team, including graduate student Joel W. Blanchard and postdoctoral research associate Jia Xie, who were lead authors, set up a library of about 100 million distinct antibodies and used it to find any that could substitute for OSKM transcription factors.
In an initial set of experiments, the researchers tried to identify antibodies that can replace both Sox2 and c-Myc. They established a large population of mouse fibroblast cells often used to make IPSCs in experiments and inserted the genes for the other two transcription factors, Oct4 and Klf4. Next they added their huge library of antibody genes to the population of cells, such that each cell ended up containing the genes for one or more of the antibodies.
The scientists could then observe which of the cells began forming stem cell colonies indicating that one of the antibodies produced by those cells had successfully replaced the functions of Sox2 and c-Myc and triggered the switch in cell identity. Sequencing the DNA of these cells allowed the researchers to determine the antibodies responsible.
In this way, the TSRI team discovered two antibodies that can be substituted for both Sox2 and c-Myc, and in a similar set of tests they found two antibodies that can replace a third transcription factor, Oct4. The scientists showed that instead of inserting these transcription factor genes they could simply supply the antibodies to the fibroblast cells in culture.
In this initial study, the scientists were unable to find antibodies that replace the function of the fourth OSKM transcription factor, Klf4. However, Baldwin expects that with more extensive screening she and her colleagues eventually will find antibody substitutes for Klf4 as well. That one I think is going to take us a few more years to figure out, she said.
The antibody-screening approach in principle allows scientists not only to find antibodies that can replace OSKM transcription factors, but also to study the natural signaling pathways through which these antibodies work.
In a proof of this principle, the scientists found that one of the Sox2-replacing antibodies binds to a protein on the cell membrane called Basp1. This binding event blocks Basp1's normal activity and thus removes the restraints on WT1, a transcription factor protein that works in the cell nucleus. WT1, unleashed, then alters the activity of multiple genes, ultimately including Sox2's, to promote the stem cell state using a different order of events than when using the original reprogramming factors.
WT1 (Wilms tumor 1) is overproduced in some cancers and is considered an oncogene. That fact highlights an added value of such studies: to help scientists understand the relationship between cancer cell development and the stem cell state.
The TSRI researchers now plan larger, more complex antibody-screening studies using human cells rather than mouse cells.
Other co-authors of the paper, Replacing reprogramming factors with antibodies selected from combinatorial antibody libraries, were Nadja El-Mecharra
Most recent headlines
04/08/2024
Dalet, a leading technology and service provider for media-rich organizations, is excited to announce Santiago Solanas as its new Chief Executive Officer (CEO)....
03/06/2024
Dalet, a leading technology and service provider for media-rich organizations, a...
28/04/2024
Mediahaus delivers the first SRT live-streaming sports production over 5G with U...
27/04/2024
On April 26, L3Harris Chair and CEO Christopher E. Kubasik joined CNBC's Mor...
27/04/2024
PORTLAND, Oregon Audinate Group Limited, the developer of the Dante AV-over-IP solution, announced significant new additions to Dante Connect, its cloud-based D...
27/04/2024
TORONTO Bell Media has launched 10 English and French-language FAST channels featuring entertainment, factual, news, and sports programming. The new free stream...
27/04/2024
An extensive new analysis of the news segments in the broadcast evening news programs of ABC, CBS, NBC and PBS has found that broadcasters devoted most of their...
27/04/2024
GERMANTOWN, Md. EchoStar's Hughes Network Systems has opened a new manufacturing facility and private 5G incubation center in Germantown, Maryland....
27/04/2024
Harry Pappas, one of three brothers who founded Pappas Telecasting Companies in 1971, died April 24. He was 78 years old....
27/04/2024
ATLANTA and LONDON Mexican telecommunications and broadcast company Televisa has selected Synamedia for an overhaul of its broadcast distribution....
27/04/2024
Participate in the Survey - The Impact of AI on Media and the Creative Industry
Pascal Wagner April 26, 2024
0 Comments
By participating in this surve...
27/04/2024
SDVI Rally Access Workstation Earns Two Top Awards at 2024 NAB Show
Brie Clayton April 26, 2024
0 Comments
SDVI, the leading platform provider for clo...
27/04/2024
Berklee's Music and Health Institute Launches Community Health Musician Cert...
27/04/2024
Charter Communications reported higher first-quarter profits despite continued cord-cutting and competition for broadband customers....
27/04/2024
Two environmentally-focused groups are partnering to engage the unscripted TV world in finding better ways to address climate change. Reality of Change is an ec...
27/04/2024
Sarah Garcia has been promoted to weekend anchor at KTLM McAllen, Texas, known as Telemundo 40. Starting April 27, she will anchor Noticias Telemundo 40 weekend...
27/04/2024
CBS Sports said it launched a new 24-hour free, ad supported streaming television (FAST) channel devoted to the UEFA Champions League....
27/04/2024
Comcast chairman and CEO Brian Roberts received $35.4 million in compensation in 2023, up 11% from the previous year, according to a proxy statement filed by th...
27/04/2024
Art Happens Here With John Lithgow, which sees the actor study dance, ceramics, silk-screen printing and vocal jazz with students in Los Angeles, debuts on PBS ...
27/04/2024
Remember Leave It to Beaver? Bewitched? Dragnet? When cable ratings were rising?...
27/04/2024
Next up for the weekend binge at Catchy Comedy is Gomer Pyle, U.S.M.C. Every weekend, Catchy Comedy features The Catchy Binge, a marathon of a classic sitcom....
26/04/2024
Sundance Film Festival CDMX 2024 kicks-off today with screenings in 5 theaters in Mexico City and the opening-night film, FRIDA, directed by Carla Guti rrez...
26/04/2024
[Editor's Note: This interview is part of a larger feature about the women d...
26/04/2024
Once again this year, SGL Carbon opened its doors to interested children and young people. On the occasion of the German Girls and Boys Day, which took place on...
26/04/2024
Orders1 of $5.5 billion; book-to-bill of 1.06x
Revenue of $5.2 billion, up 17%,...
26/04/2024
Five Considerations For Communications Modernization In The 21st Century
In the digital-enabled battlespace, the Joint Force needs to shoot, move and communica...
26/04/2024
CBS Sports has launched Champions League as a new, 24-hour streaming channel that will serve as the year-round destination for nonstop highlights of the UEFA ...
26/04/2024
Despite tough competition in the streaming space, Roku reported solid results in Q1 2024, beating revenue expectations, with total net revenue up 19% YoY to $88...
26/04/2024
LONDON AND TORONTO Pinewood Toronto Studios has appointed Sarah Farrell as general manager of the Studios in downtown Toronto....
26/04/2024
Quantum to Offer Advanced Filesharing Technology and Performance in StorNext and...
26/04/2024
FilmLight Colour Awards welcomes 2024 entries and introduces new Emerging Talen...
26/04/2024
Picture Shop Announces Chris Evans as Head of Unscripted
Brie Clayton April 26, 2024
0 Comments
Picture Shop announced Chris Evans will lead Unscripte...
26/04/2024
Participate in a Survey - The Impact of AI on Media and the Creative Industry
Pascal Wagner April 26, 2024
0 Comments
By participating in this survey,...
26/04/2024
Toy maker Mattel said it is working with Samsung to launch its first free ad-supported streaming television (FAST) channels later this year....
26/04/2024
Trusted Media Brands (TMB) said it named Marty Moe as president....
26/04/2024
Ron Howard is the director on Jim Henson Idea Man, a documentary that premieres on Disney Plus May 31. Henson of course created Kermit the Frog, Miss Piggy, Big...
26/04/2024
The ice continues to melt under the regional sports network business as the Seattle Kraken of the National Hockey League have made a long-term deal to broadcast...
26/04/2024
Heading into the upfronts, Warner Bros. Discovery said it launched Olli, a first-party data platform advertiser can use for converged, targeted advertising camp...
26/04/2024
CBS has renewed the drama The Equalizer, which will see season five on in 2024-2025. Queen Latifah stars....
26/04/2024
The CW has entered into an exclusive multiyear broadcast partnership for the Miss USA Pageant and the Miss Teen USA Pageant. The 73rd Miss USA Pageant will air ...
26/04/2024
Fuse Media isn't mincing words in a campaign urging its young viewers to register and participate in the 2024 elections....
26/04/2024
Dead Boy Detectives, a series from Neil Gaiman about a detective agency staffed by ghosts, debuts on Netflix April 25. George Rexstrew and Jayden Revri are in t...
26/04/2024
The Story Collective has gradually repurposed the former Mortlake Brewery to include production offices, workshops and sound stages
By Matthew Corrigan
Publi...
26/04/2024
Perkett joins the company following a 25 year career in product management, product marketing, engineering and user experience (UX) across multiple industries
...
26/04/2024
Teradek, the industry leader in wireless video transmitters and receivers, announced today the launch of new Bolt 6 LT 750 and Bolt 6 Monitor Module 750 RX with...
26/04/2024
NEW YORK Amagi has appointed Richard Perkett chief product officer (CPO)....
26/04/2024
WASHINGTON, D.C. The National Association of Broadcasters (NAB) has announced the results of the 2024 NAB Radio and Television Board of Directors elections. The...
26/04/2024
EL SEGUNDO, Calif. & NEW YORK Mattel has announced a deal to launch its first three 24/7 free ad supported streaming (FAST) channels on Samsung TV Plus, Samsung...
26/04/2024
PORTLAND, Maine Viewers here can now receive the NextGen TV signals of five local stations with the launch of ATSC 3.0 service from host station WPFO, which is ...
Outside-In Reprogramming: Antibody Study Suggests a Better Way to Make Stem Cells 
