Turning it up a Notch
Notch is a very interesting molecule. It acts as a receptor (for ligands such as Serrate), as well as a transcription factor when activated. The role of Notch in assigning tissue fate is established across the animal kingdom.
A patent at StemCellPatents.com # 7,138,276, entitled Differentiation-suppressive polypeptide serrate-2 and methods of use teaches that Notch ligands inhibit differentiation of hematopoietic stem cells.
A recent paper demonstrated using the retinal stem cell development model, that in order for retinal stem cells to develop either into glial cells or neurons, they must down-regulate Notch expression (Jadhav et al. Notch activity permits retinal cells to progress through multiple progenitor states and acquire a stem cell property. Proc Natl Acad Sci U S A. 2006 Dec 5).
This is in agreement with other papers that demonstrate Notch activation promotes self renewal of stem cells but not differentiation. For example, it is known that another Notch ligands are expressed by bone marrow stromal cells and are important in maintaining bone marrow hematopoietic stem cell self-renewal properties (Li et al. The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1. Immunity. 1998 Jan;8(1):43-55).
Interestingly, Notch activating peptides exist such as the Delta/Serrate/LAG-2 domain of human Jagged1 (CDDYYYGFGCNKFCRPR) which can be added to cells to act as Notch receptor agonists and inhibit differentiation.
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SSlavin said...
I dont know, but i saw a paper by Liu et al describing embedding DSL peptides in artificial matrices for stem cell implantation.
J Hematother Stem Cell Res. 2003 Dec;12(6):689-99.
Paul said...
I did find one about Notch ligand on MOBILIZED hematopoietic stem cells actually inducing CD4+ CD25+ t regulatory cells...this is very strange since mobilizors of hematopoietic stem cells have previously been reported to protect from autoimmunity...for example G-CSF...
This paper is a must-read... Jagged2-expressing hematopoietic progenitors promote regulatory T cell expansion in the periphery through notch signaling
notch1 said...
to Paul -
that's very nice paper! thank you
About iv administration of notch signaling molecules nobody publish yet (in my knowledge), but there is very nice paper about using Delta1-Fc chimeric protein (this is second ligand for Notch1-4 family, first is Jagged2) for HSC expansion ex vivo and this protein is availible.
https://stemcells.alphamedpress.org/cgi/content/abstract/24/11/2456
Also as far as i know Notch-signaling not only caused HSC expansion and self-renewal but act on differentiation hematopoietic cells, such as stimulate differentiation HSC from ES and T-cells from HSC, inhibit B-cell differentiation. As you know widely used OP-9 stromal cell line for HSC derivation from ES and T-cells from HSC & ES - based on Notch-signaling pathway.
notch1 said...
there is OP-9 expressed notch ligand - Delta-like-1 = OP-9-DL-1
Schmitt, T.M. et al. (2004) Nat. Immunol. 5:410.
https://www.rndsystems.com/DAM_public/5482.jpg
but i don't know it's commercially availible or not,
i'm actuaaly not sure about usual OP-9 (credit: T Nakano) what you can get from ATCC
second part of your question i can't answer, i work in a bit different area
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Paul said...
Can Notch activating peptides be administered in vivo? Has anyone used the Notch pathway therapeutically?