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
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
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
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.