Stem Cells Don't have to be Alive to Be Beneficial

Discussion of Hoffmann et al. Thorac Cardiovasc Surg. 2010 Apr; 58(3):136-142

The use of stem cells in patients who have poor circulation is well-known.  In fact, the first use of stem cells for conditions other than blood disorders was in patients who were undergoing bypass surgery.  Usually patients undergo bypass because of advanced atherosclerosis that is inhibiting the flow of blood to the heart muscle.  Despite success of bypass surgery, the underlying problem of thickened blood vessels remains.  Japanese scientists (Hamano et al. Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart disease: clinical trial and preliminary results. Jpn Circ J. 2001 Sep;65(9):845-7) in 1999 treated 5 patients with ischemic heart disease with their own bone marrow cells injected into the heart muscle during bypass.  Of these 5 patients, 3 demonstrated increased blood flow at the area where the stem cells were injected.  Subsequent to this numerous clinical trials have been conducted using bone marrow stem cells for increasing circulation both to the heart and also to legs that lack proper blood flow (particularly in patients with critical limb ischemia see video http://www.youtube.com/watch?v=dcCwZ4CsiKc ). 

One of the major questions has always been how the injected stem cells improve circulation.  Originally the idea was that the stem cells become new blood vessels, and that these new blood vessels take over the function of the older blood vessels.  However, recent data suggests that the stem cells injected actually collaborate with the stem cells that are already in the patient.  For example, it was demonstrated that in patients lacking oxygen in their legs who receive bone marrow stem cell therapy, the responders actually have increased levels of their own circulating stem cells.  Here is a video describing this http://www.youtube.com/watch?v=OwIOL13vXQ4.

It is believed that bone marrow stem cells, particularly mesenchymal stem cells, are capable of producing proteins that stimulate the body's own stem cells into making new blood vessels.  These proteins include IGF-1, VEGF, and HGF. 

A recent study from Stanford University (Hoffmann et al. Angiogenic Effects Despite Limited Cell Survival of Bone Marrow-Derived Mesenchymal Stem Cells under Ischemia. Thorac Cardiovasc Surg. 2010 Apr;58(3):136-142) should to investigate the cellular and molecular interactions which are associated with formation of new blood vessels after administration of bone marrow mesenchymal stem cells.

The investigators first began by assessing production of the protein VEGF from bone marrow mesenchymal stem cells under conditions of normal oxygen, and under reduced oxygen conditions.  The idea being that if mesenchymal stem cells are responsible for producing growth factors, then it would make sense that production of these factors would increase in response to needs of the body (eg reduced oxygen).  As a control, fibroblast cells were assessed side by side with the mesenchymal stem cells.  It was found using in vitro experiments that mesenchymal stem cells produced much higher levels of VEGF under hypoxia as compared to fibroblasts, however, mesenchymal stem cells died faster than fibroblasts in response to hypoxia.

To determine whether mesenchymal stem cells or fibroblasts cause formation of new blood vessels in animals, a model of critical limb ischemia was developed in which the artery feeding the leg of mice was ligated. 

One week after induction of ischemia in the leg, 1 million mesenchymal stem cells, or fibroblasts were injected into the muscles of the animals.  The cells were labeled genetically so that the injected cells could be distinguished from the endogenous cells. 

Substantially elevated levels of new blood vessels, and improved circulation, was observed in the mice that received mesenchymal stem cells as compared to fibroblasts.  Interestingly, at 3 weeks after administration, despite improved circulation, the mice receiving mesenchymal stem cells had much lower numbers of injected cells as compared to mice that received fibroblasts.

This study suggests that mesenchymal stem cells seem to use the natural mechanisms of the body in order to generate new blood vessels.  Something else of interest from this study is that fibroblasts live longer in hypoxia as compared to mesenchymal stem cells.  Hypothetically it may be possible to transfect fibroblasts with genes that stimulate production of new blood vessels.  Unfortunately, the proper combination of growth factors and concentration are still not known for creation of new blood vessels.