Transient Inhibition of Transforming Growth Factor-{beta}1 in Human Diabetic CD 34+ Cells Enhances Vascular Reparative Functions

Bhatwadekar et al. Diabetes. 2010 May 11

CD34 cells are primarily known for their hematopoietic activity, which means, that they are capable of making blood cells. More recently, studies have demonstrated that a subset of CD34 cells are capable of creating new blood vessel cells called endothelial cells. The ability to made new endothelial cells is important because old/dysfunctional blood vessel cells contribute to risk of stroke or heart attack.

Numerous disease conditions can benefit from increasing the number of healthy new blood vessels. Accordingly, studies have been conducted taking out patient bone marrow cells (which contain high concentrations of CD34 cells) and administering them either intravenously or locally in order to stimulate new blood vessel formation. This procedure has been helpful in patients with advanced peripheral artery disease www.youtube.com/watch?v=OwIOL13vXQ4 , as well as in patients with heart failure www.youtube.com/watch?v=flv0RmzPyLU. There are several companies using patient's own bone marrow as a source of stem cell therapy after manipulation, these include Aldagen, Baxter, Amorcyte, Micromet, and Harvest-Tech.

Unfortunately there is a problem with the bone marrow cells of patients with diabetes or other inflammatory conditions: the cells don't work as well at making new blood vessels as compared to cells of healthy patients. One of the reasons for this is believed to be high concentrations of circulating TGF-beta in the blood of type 2 diabetics. This protein is known to suppress stem cell multiplication and is associated with the body trying to inhibit inflammation.

The study discussed in the paper Bhatwadekar et al. experimentally suppressed TGF-beta in CD34 cells from diabetic patients and asked whether this could restore the ability of the CD34 cells to generate new blood vessels.

The scientists used an artificially designed inhibitor technology called "morpholino antisense oligonucleotides" to treated CD34 cells. They demonstrated >90% suppression of TGF-beta production in the cells from diabetic patients. It was found that after inhibition of TGF-beta the ability of the CD34 cells to produce new blood vessels was substantially increased. This was demonstrated in the retinal ischemia reperfusion injury model in the mouse.

At a mechanistic level it appears that the therapeutic effects of TGF-beta inhibition were associated with increased ability to migrate to area of needed. This was demonstrated by higher expression of the receptor CXCR-4.