Some thoughts on hematopoietic reprogramming

by Alexey Bersenev on April 30, 2014 · 1 comment

in direct reprogramming,hematopoietic

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We all hear “cells ABC were converted into cells DEF to treat condition XYZ”. Reprogramming is very hot topic right now! There are a lot of proof-of-concept studies, which demonstrate “we can do it!” But the question is “Will it move toward clinical translation?”

A new study, published last week, demonstrated for the first time a possibility of reprogramming hematopoietic progenitor cells into hematopoietic stem cells (iHSC). All previous attempts to generate functional HSCs from different cell types via reprogramming by defined factors are failed. The study is well done and solidified by great assays. We finally have an answer – “yes, we can do it!” However, I’d put my doubt on following claim “…blood cell reprogramming may be a strategy for derivation of transplantable stem cells for clinical application”. And of course I don’t like media hype around it – “New hope in regenerative medicine“. Reading through the paper, I realize how difficult and nearly impossible potential clinical application could be. I’d like discuss just 3 considerations here.

  1. What is competitive advantage of generating HSC by reprogramming of blood progenitors with 8 factors over other techniques? The authors mentioned, that other methodologies, involved pluripotent stem cells, were not able to generate transplantable HSC. But it’s not true. For example, famous Ledran’s study, was not cited in the paper (Orkin: “In the blood-research field, no one has the conditions to expand HSCs in the tissue culture dish”). Suzuki’s study, which demonstrated generation of engraftable iPS-teratoma-derived HSC in vivo, was also not cited.
  2. How Rossi’s findings will be translated to human cells and generation of functional HSC ex vivo? It seem to me that media, which covered the study, completely missed this point – HSCs were generated in vivo! Both questions mentioned in the paper.
  3. Taking in account, that 6 out of 8 used transcription factors are proto-oncogenes, who is willing to take a risk for “massive genetic manipulation” in order to get a few iHSC? Remember, in real hematology clinic, starting material – hematopoietic progenitors – more likely will carry mutations, which inherited from HSCs.

Well, before having a discussion about practicality, every “reprogramming study” should be reproduced first. I’m following this field since the begining, but I don’t remember any reproduced study. Take famous Bhatia’s study of 2010 – it was a big buzz, but what is the progress? Remember iHem cells? Any reproducibility effort in the last 9 months? Is it moving forward?

Please discuss with me the promise and challenges of hematopoietic reprogramming, starting from simple question – What is the point? I hope you can break my skepticism and convince me.

{ 1 comment… read it below or add one }

CJ Chang May 1, 2014 at 9:12 pm

I think it is a proof of principle that the TFs can transverse somatic cell into stem cells. However, same as iPS cell at beginning, used oncogene such as c-myc. The method can be improved by transgene free methods. However, Base on the dynamic of HSCs other than ESCs, it’s hard to keep long-term culture of HSCs in the dish. if continuously express those factors can help to keep the self-renewal of HSCs in the dish by playing around these factors will be amazing in the field.
Also, I am totally agree with you that most of the iHEM, etc, lacking of data to show the reproductivity will be a problems.
Other issue I would like to know is if same TF combination can be applied to human cells.
these are some of my thought.

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