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October 03, 2008

MUC1 Protein Mediates the Growth of Human Pluripotent Stem Cells, Stem Cell Treatment and Cancer Breakthrough


The cleaved form, MUC1*, is expressed on undifferentiated human embryonic stem cells while the full-length, uncleaved protein (MUC1-FL) is expressed on differentiated stem cells.

These studies represent a big step forward for human stem cell research and the future of stem cell transplantation. Previously Minerva Biotechnology reported that the MUC1 protein exists in the same altered form, MUC1*, on over 75% of human cancers. Genetically engineered stem cells have the potential to rejuvenate the human body, cure diseases and extend life. Stem cells seem to be key to the rejuvenation of the immune system, muscles and the cornea.

Minerva Biotechnologies and the University of California at Santa Barbara discovered that a single, new growth factor can not only support massive growth of human embryonic stem cells (hESCs) in vitro, but also maintains them in a nearly 100% undifferentiated state without the need for fibroblast "feeder cells". This represents a major step forward for potential stem cell therapies as well as in the basic understanding of the mechanisms that regulate stem cell growth and differentiation.







We have shown that undifferentiated embryonic stem cells do not express full-length MUC1. Rather, they express a low molecular weight cleavage product, MUC1*, which we previously demonstrated has growth factor receptor-like activity on tumor cells. NM23, which was shown to be an activating ligand of MUC1* on cancer cells, co-localizes with MUC1* on pluripotent cells. Unexpectedly, we found that newly differentiated cells no longer express cleaved MUC1* or its ligand, NM23. Newly differentiated stem cells present full-length MUC1. Transition zones between undifferentiated and differentiating cultured stem cells can be found that continue to express OCT4, while also expressing uncleaved, full-length MUC1, which appears to be a marker for the onset of differentiation. Thus, the switch from cleaved MUC1* to the full-length protein may be one of the first detectable signals of the onset of differentiation. These results imply that MUC1* may be a more accurate marker of pluripotency than OCT4 and thus antibodies that recognize MUC1* could be used to search for, identify and isolate pure populations of pluripotent stem cells. Anti-MUC1* has been used extensively in our labs to effectively identify and sort both live and fixed MUC1*-positive cancer cells using FACS. These methods can be readily extended to identifying and sorting live embryonic stem cells, which could automate and improve the procedure for separating out stem cells that remain pluripotent from those that have begun to differentiate. At present this is an imprecise and labor-intensive process that depends on the technician's ability to visually discriminate between cell types then manually dissect pluripotent cells without contaminating the pool with cells that have already entered the differentiation process.

As on cancer cells, MUC1* functions as a growth factor receptor on pluripotent embryonic stem cells. Under conditions that included adding conditioned media from fibroblast feeder cells, antibody-induced dimerization of the extracellular domain of MUC1* stimulated the growth of hESCs more than two-fold better than current methods and importantly without requiring the addition of exogenous bFGF. Further, the addition of MUC1* dimerizing ligands, Anti-MUC1* or NM23, enabled the growth of pluripotent stem cells in feeder-cell-free and bFGF-free minimal growth media. In fact, stem cell growth supported by the addition of MUC1* ligands to minimal media resisted spontaneous differentiation and produced more pluripotent cells than any other growth condition that we tested. In contrast, neither minimal stem cell growth media nor media plus bFGF produced any undifferentiated stem cells. Stem cells that were cultured in conditioned media from fibroblasts plus bFGF generated a mixture of undifferentiated and differentiated colonies and the colonies were smaller than those produced by MUC1* stimulation. Thus, in addition to mediating the growth of embryonic stem cells, MUC1* may be a modulator of differentiation. The data presented strongly suggest that MUC1* is a critical marker for the identification and isolation of pluripotent embryonic stem cells as well as a key mediator of the growth and differentiation of pluripotent stem cells.


FURTHER READING
Stem cell transplantation is discussed at wikipedia

Immunology and stem cells could be combined to rejuvenate and re-program the immune system for better health.

Genetically tweaked stem cells reacted to biochemical signals to revive the ability of muscle tissue in old mice to repair itself nearly as well as the muscle in the mice's much younger counterparts. [Genetically engineered stem cells were used to rejuvenate muscles. Make old muscles young]

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