Enhanced growth of adult stem cells with Dkk-1

Patent Number: 7,485,460

Although mesenchymal stem cells, or mesenchymal stromal cells (as some others call them), are in late stages of clinical development, there is still room for optimizing their therapeutic effects. 

For example, various groups have transfected MSC with genes such as nanog or bcl-2 or CD49d, modified culture conditions (hypoxia or acidity), or exposed them to hormones in order to increase homing, regenerative activity, or antiinflammatory effects.

The current patent covers the use of Dkk-1 to expand the number of pluripotent MSC.  It should be stated that numerous current expansion conditions, although they expand cells that look like MSC based on phenotypic markers (eg CD90, 105 positive, CD14, 34, 45 negative), the cells lose pluripotent ability upon expansion.  Therefore the inventors of the current patent have figured out a method of inducing expansion not only of cells that look like MSC, but ones that actually retain the functional characteristics of pluripotent cells.

The first independent claim of the patent reads as follows:

"A method for expanding multipotential bone marrow stromal cells cultured in vitro, said method comprising adding an effective amount of Dkk-1 to the growth medium in which said bone marrow stromal cells are cultured, thereby increasing the number of multpotential bone marrow stromal cells." 

Now you may be wondering, like I am, "what is Dkk-1?"

From reading the specification, it says that Dkk-1 is the abbreviation for Dickkopf-1, an inhibitor of the Wingless (Wnt) signaling pathway.  This pathway is involved in numerous self-renewal activities.  The specification states that an increase in Wnt signaling has been shown to increase proliferation of hematopoietic stem cells from bone marrow (Austin, et al., Blood 89:3624-3635, 1999).  Perhaps most interesting, the specification states that during log phase growth of MSC, there is increased secretion of Dkk-1, which stops when the MSC slow down their self-renewal.

Wnt signalling is involved in self renewal of cancer stem cells.  Indeed maybe the secretion of Dkk-1 by proliferating MSC may explain some of the data showing MSC inhibit cancer.  This is supported by two publications (Zhu Y et al. Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1. Leukemia 2009 Jan 15) and (Qiao et al. Dkk-1 secreted by mesenchymal stem cells inhibits growth of breast cancer cells via depression of Wnt signalling. Cancer Lett. 2008 Sep 28;269(1):67-77).

View this patent on the USPTO website.