Why the hype about in vivo reprogramming?

Sunday August 31st, 2008 @ 17:08:24 EST

From Category: Differentiation

Cambridge, MA-

You may have seen the widespread media coverage last week describing the "reprogramming" of pancreatic cells into insulin producing "islet-like cells". Essentially, all the buzz was about a paper (Zhou et al. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 2008 Aug 27) in which differentiated pancreatic exocrine cells (not the ones that make insulin) were made to express Ngn3, Pdx1 and Mafa, which caused the cells to resemble beta cells and most importantly revert diabetes.

Now this is an important finding BUT, readers of StemCellPatents.com will know that the use of some of these transcription factors for inducing production of insulin from non-insulin producing cells has already been covered in US patent #7,323,165, which is assigned to the University of California. For example, in that patent, one of the supporting data included recovery of a streptozotocin-induced diabetes model after in vivo viral delivery of ngn3 !!

Interestingly, the other transcription factor used by the researchers, Pdx1, has also previously been used to induce expression of insulin, this time in mesenchymal stem cells.

So while the finding may have caught international attention, the concepts behind the finding appeared to us to be nothing new...we welcome comments since maybe we misunderstood something....


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2 Comments | Add Comment

jonnyboy said...

Created 2008-09-01 13:51:06 EST

The buzz was because of several reasons.  First of all the name of the senior author is highly well known and recognized and so was the journal.  Secondly, the degree of efficacy seemed to be higher than the efficacy in the patent that was cited by the University of California group.

While the finding of this transdifferentiation is very potently therapeutic, what is very interesting is other work that demonstrated plasticity of adult cells changing from one type to another by transfection of the cytoplasm.  In your description of a patent on this website you talk about the work of a guy named Collas who was able to transition fibroblasts to a cellular entity that resembled a T cell through the administration of T cell cytoplasmic extract into the fibroblast.  They made the fibroblast to actually express the T cell receptor and more interestingly when the T cell receptor was crosslinked the fibroblast was actually making interleutkin-2, just like a T cell would.

This is because undefined factors in the differentiated cell are able to alter the nucleaus of other celsl to differentiate.  The importance of the work of Melton was that he was able to concretely define some of the factors and find a synergy that resembles embryonic development. 

Like stemcellpatents.com pointed out, people have made mesenchymal stem cells secrete insulin by transfecting with pdx-1.  So I wonder what would happen if you transfected mesenchymal stem cells with the combo of ngn3, pdx-1 and MAFA.  But then again the people at harvard do not like adult stem cells so they would rather stick with playing around with viral vectors and teratogenic embryonic stem cells. 

In any case, one thing we all agree on: We truly live in exciting times. 

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StemCellPatents.com said...

Created 2008-09-10 09:06:15 EST

For those of you who are interested, the stunning work involving "reprogramming" with cytoplasmic transfer can be seen in the abstract below.

 

Nat Biotechnol. 2002 May;20(5):460-6. Links

Comment in: Nat Biotechnol. 2002 May;20(5):445-6. Reprogramming fibroblasts to express T-cell functions using cell extracts.Håkelien AM, Landsverk HB, Robl JM, Skålhegg BS, Collas P.

Institute of Medical Biochemistry, P.O. Box 1112, Blindern, University of Oslo, Oslo 0317, Norway.

We demonstrate here the functional reprogramming of a somatic cell using a nuclear and cytoplasmic extract derived from another somatic cell type. Reprogramming of 293T fibroblasts in an extract from primary human T cells or from a transformed T-cell line is evidenced by nuclear uptake and assembly of transcription factors, induction of activity of a chromatin remodeling complex, histone acetylation, and activation of lymphoid cell specific genes. Reprogrammed cells express T cell specific receptors and assemble the interleukin-2 receptor in response to T cell receptor CD3 (TCR CD3) complex stimulation. Reprogrammed primary skin fibroblasts also express T cell specific antigens. After exposure to a neuronal precursor extract, 293T fibroblasts express a neurofilament protein and extend neurite-like outgrowths. In vitro reprogramming of differentiated somatic cells creates possibilities for producing isogenic replacement cells for therapeutic applications.

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