What’s the Noggin ?

Noggin is a disulfide-linked homodimer that binds to TGF-family members and prevents them from signaling through their receptors. ^[1] By blocking bone morphogenetic protein 4 (BMP-4) and other BMPs' signaling pathways, noggin is essential in controlling developmental processes. For example, noggin helps maintain human embryonic stem cells that have not yet differentiated in culture and can be utilized temporarily to stop spontaneous differentiation. The dorsal mesoderm produces noggin, which is also crucial for the development of healthy bone and neural tissue throughout embryogenesis. Additionally, it affects the development of chondrogenesis, osteogenesis, and joints and encourages the differentiation of embryonic stem cells into dopaminergic neurons and their subsequent survival.^[2]
 



Role of noggin in cell culture

In some adult organs, like the liver, proliferating cells are typically not plentiful. However, the liver possesses a remarkable capacity for regeneration after injury, which is followed by the appearance of Lgr5-positive stem cells. These cells can be extracted and cultured in vitro as organoids. And the researchers found that compared to the liver itself, the gallbladder is a more abundant source of stem/progenitor cells which can be cultured in culture as organoids for more than a year through presenting in R-spondin 1 and noggin. In contrast, when these growth factors were absent, the organoids partially differentiated toward the hepatocyte fate. This discovery indicates future research on liver-related genetic illnesses and chronic liver insufficiency may benefit from the differentiation of gallbladder-derived stem cells into hepatocytes and transplantation into patients.  ^[3-4] Moreover, numbers of studies show that noggin synergizes with basic fibroblast growth factor (bFGF) to inhibit BMP signaling and maintain the undifferentiated proliferation of human embryonic stem cells (hESCs). ^[5-6] These findings assist the researchers in resolving the issues about spontaneous differentiation and the potential of animal infections spreading during the therapeutic application, as opposed to routinely cultivating the hESCs on mouse embryonic fibroblast (MEF) feeders.
 


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Ref.

1. Groppe J, Greenwald J, Wiater E, Rodriguez-Leon J, Economides AN, Kwiatkowski W, Affolter M, Vale WW, Izpisua Belmonte JC, Choe S. Structural basis of BMP signaling inhibition by the cystine knot protein Noggin. Nature. 2002 Dec 12;420(6916):636-42.
2. Brunet LJ, McMahon JA, McMahon AP, Harland RM. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science. 1998 May 29;280(5368):1455-7.
3. Lugli N, Kamileri I, Keogh A, Malinka T, Sarris ME, Talianidis I, Schaad O, Candinas D, Stroka D, Halazonetis TD. R-spondin 1 and noggin facilitate expansion of resident stem cells from non-damaged gallbladders. EMBO Rep. 2016 May;17(5):769-79.
4. Hacker DL, Ordóñez-Morán P. Large-Scale Production of Recombinant Noggin and R-Spondin1 Proteins Required for the Maintenance of Stem Cells in Intestinal Organoid Cultures. Methods Mol Biol. 2020;2171:171-184.
5. Chaturvedi G, Simone PD, Ain R, Soares MJ, Wolfe MW. Noggin maintains pluripotency of human embryonic stem cells grown on Matrigel. Cell Prolif. 2009 Aug;42(4):425-33.
6. Xu RH, Peck RM, Li DS, Feng X, Ludwig T, Thomson JA. Basic FGF and suppression of BMP signaling sustain undifferentiated proliferation of human ES cells. Nat Methods. 2005 Mar;2(3):185-90.
7. Wang G, Zhang H, Zhao Y, Li J, Cai J, Wang P, Meng S, Feng J, Miao C, Ding M, Li D, Deng H. Noggin, and bFGF cooperate to maintain the pluripotency of human embryonic stem cells in the absence of feeder layers. Biochem Biophys Res Commun. 2005 May 13;330(3):934-42.