4 October 2004. Stem cells: Science…or science fiction? Often lost in all the political hoopla are the scientific reservations about whether stem cells can truly—and safely—replace decrepit or dead cells in vivo (see ARF Live Discussion). Two reports in the October issue of the journal Stroke both buttress the case for stem cell promise and underscore that logistical issues are finally going to determine the fate of stem cells in medicine.
Both studies find that human umbilical cord stem cells, injected into the bloodstream, can protect brain cells and rescue behavioral deficits in a rat model of stroke—all without ever taking up residence in the brain. In one study, first published online August 19, 2004, Alison Willing, Martina Vendrame, and colleagues at the University of South Florida in Tampa showed that the behavioral rescue was dose-dependent. The highest doses transfused (>107 blood cells, a subset of which are stem cells) were also able to reduce pathology associated with ischemic damage. Interestingly, first author Vendrame and colleagues found almost no sign of the progeny of transfused human stem cells in the brain, and the few cells detected were mostly in blood vessels.
So what are these stem cells doing for the brain from afar?
A second article, originally published online September 2, 2004, by Cesar Borlangan of the Medical College of Georgia in Augusta, along with some of the same authors from the Vendrame paper, suggests that the cord stem cells are secreting growth factors such as GDNF to protect neurons (see ARF related news story on GDNF as a therapeutic for Parkinson’s disease and ARF related story). Borlangan and colleagues used the same rat stroke model, but rather than waiting 24 hours after the experimental lesion as Vendrame and colleagues had done, they infused cells during the procedure. What’s more, they pried open the notoriously tight blood-brain barrier (BBB) using mannitol. This protocol produced reductions in behavioral deficits and pathology, accompanied by a 68 percent increase in brain GDNF three days after the surgery. Transient increases in NGF and BDNF were seen on day one, but were not sustained. Without the mannitol to permeabilize the BBB, there was no increase in brain neurotrophic factors. And, as in the Vendrame et al. study, there was no evidence that the stem cells had made it to the brain.
In order to determine whether this extra GDNF was derived from the stem cells, as opposed to endogenous sources, Borlangan and colleagues pre-exposed the cord blood to antibodies against all three neurotrophic factors. This manipulation blocked the brain GDNF increase, as well as the behavioral and neuroprotective benefits.
The fact that peripheral stem cells did not need to enter the brain, much less the lesion area, to protect brain cells might have significant implications for some of the failed studies of stem cell transplants in human trials (see ARF related news story on Parkinson disease). In some of these cases, clinical benefits were seen even when the grafts did not survive, findings that were dismissed as a placebo effect. “In the end, our study shows that in addition to detecting grafted cells, trophic factor elevation in the brain is a major index of transplant-induced neuroprotection,” write the authors.
The approach used by Borlangan and colleagues may also mitigate a concern expressed by Vendrame and colleagues, who had found that a relatively large number of umbilical cord blood cells were required to show histological evidence of protection from ischemic brain damage. The most effective doses in the Vendrame et al. protocol (>107 blood cells per rat) would require the blood from more than 20 human umbilical cords to treat a single human being. The method employed by Borlangan et al.—infusing cord blood cells sooner and using mannitol to permeabilize the BBB—produced benefits with “only” 2 x 105 blood cells.—Hakon Heimer.
Borlongan CV, Hadman M, Sanberg CD, Sanberg PR. Central nervous system entry of peripherally injected umbilical cord blood cells is not required for neuroprotection in stroke. Stroke. 2004 Oct;35(10):2385-9. Epub 2004 Sep 02. Abstract
Vendrame M, Cassady J, Newcomb J, Butler T, Pennypacker KR, Zigova T, Sanberg CD, Sanberg PR, Willing AE. Abstract Infusion of human umbilical cord blood cells in a rat model of stroke dose-dependently rescues behavioral deficits and reduces infarct volume. Stroke. 2004 Oct;35(10):2390-5. Epub 2004 Aug 19. Abstract