Adult Stem Cells and the Treatment of Stroke

Taken from: The Therapeutic Potential of Stimulating Endogenous Stem Cell Mobilization

Many studies have shown that extensive neuronal death in the brain after a stroke triggers the migration of neural stem cells to the site of injury, followed by their proliferation and differentiation into neurons and glial cells (Peterson, 2002; Fallon et al., 2000; Arvidsson et al., 2002; Nakatomi et al., 2002; Schmidt and Reymann 2002).

However, this natural process does not appear to be sufficient to produce significant functional recovery (Yamamoto et al., 2001; Magavi and Macklis, 2002).

As with the heart after acute myocardial infarction, stroke has been associated with bone marrow stem cell mobilization. Studies have shown that the number of peripheral blood stem cells in stroke patients can increase up to 3-fold within 7 days after the stroke (Hennemann et al., 2008; Paczkowska et al., 2005). In one study, the magnitude of BMSC mobilization was correlated with the patients' functional recovery (Dunac et al, 2007).

When rats were injected with rat (Chen et al., 2001; Pavlichenko et al., 2008; Willing et al., 2003) or human stem cells (Li et al. 2002) after an induced stroke, significant motor and cognitive improvements were observed. Although a significant number of bone marrow-derived cells could be identified as newly formed neurons and glial cells in the stroke foci, they accounted for only a small percentage of the total number of newly formed brain cells.

Most of the newly formed brain cells are believed to be derived from neural stem cells upon the action of paracrines secreted by the migrating stem cells. Similar results were obtained using human umbilical cord stem cells (HUCSCs) where intravenous injection of HUCSCs 24 hours after a stroke greatly improved functional recovery (Chen et al., 2001). Injection of HUCSCs 7 days after the stroke still led to significant functional recovery, though the extent of the recovery was less than with treatment at 24 hours.

Mobilization of bone marrow stem cells induced by G-CSF was shown in a number of studies to improve the outcome of a stroke. For example, when tested 14 and 28 days after a stroke, animals treated with G-CSF showed much greater body coordination than control animals (Shyu et al., 2004).

When the brains were analyzed using imaging, the infarcted area was much smaller in the treated group (61 mm3) when compared to the control group (176 mm3). All these benefits were greatly reduced when the animals were pre-treated with a blocker of CXCR4, indicating that the observed effects were dependent upon the migration of bone marrow stem cells into the brain.

Similar results have been reported by other scientific teams (Six et al., 2003; Kawada et al., 2006). For example, after repopulating the bone marrow with green fluorescent protein-positive stem cells, GCSF-induced bone marrow stem cells mobilization immediately and roughly 2 weeks after inducing a stroke dramatically improved motor and cognitive performances four weeks after the stroke, as measured by using the Morris water maze (Kawada et al., 2006).

In this study, while all the mice in the treated group reached the platform within 40 seconds, none of the control mice reached the submerged platform within the allotted 120 seconds. As in the study by Shyu et al. (2004), the infarct size was much smaller in the treated animals when compared to control. Using BrdU it was observed that the number of new brain cells found in the infarcted area was much higher in the treated group than in the control group.

Yet very few of the new brain cells were green fluorescent protein-positive, supporting the view that as they migrate in the brain bone marrow stem cells secrete growth factors that support the proliferation and differentiation of neural stem cells (Yoo et al., 2008). Bone marrow stem cells also support neovascularization, which further contributes to the regeneration of the brain tissue (Lee et al., 2005; Hess et al., 2002; Kan et al., 2005).

Although much of this work needs to be reproduced in humans, endogenous stem cell mobilization for the treatment of stroke appears promising and would constitute a safe approach to the treatment of stroke.

Clinical application: Cerebrovascular accident (Stroke)

In September 2008, GE, a 78 year old male surgical oncologist who was otherwise in good health, had a stroke. The MRI/MRA revealed an acute infarct involving the right lentiform nucleus, moderately extensive chronic small vessel ischemic changes, chronic lacunar infarct involving the right ventromedial thalamus, and intracranial atherosclerotic vascular disease.

The stroke left GE with aphasia and a reduced ability to perform any physical activity. October 2009, 13 months after the stroke, GE began taking StemEnhance; GE consumed 1 gram twice per day and after 8 weeks on the product GE noticed improvement with his speech and experienced more energy with improved balance.

In April 2010 a repeat MRI/MRA showed no evidence of an acute infarct. GE's aphasia was completely resolved at this point and his overall mobility was improved allowing him to perform all activities of daily living. In January of 2011 a repeat MRI/MRA of the anterior and posterior cerebral arteries demonstrated no evidence of hemodynamically significant stenosis, and revealed normal vertebrobasilar arteries with no evidence of intracranial aneurysm or vascular malformation.

To date, GE has resumed playing tennis at age 81, walks around the mall in the neighborhood with other senior citizens and has returned to his professional activity as a surgeon.

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