Progenitor cell therapies as a novel treatment for traumatic brain injury: a pathway towards neuroprotection

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Date: Sept. 2011
From: Therapy(Vol. 8, Issue 5)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 1,866 words
Lexile Measure: 1460L

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Author(s): Peter A Walker 1 , Shinil K Shah 2 , Charles S Cox [[dagger]] 3

KEYWORDS

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inflammation; mesenchymal stromal cells; neuroprotection; progenitor cells; traumatic brain injury

Traumatic brain injury (TBI) places a tremendous burden upon the American healthcare system and is associated with significant longterm patient morbidity [1] . In addition, all acute monotherapies focused on maintaining cerebral perfusion have failed to reverse the neuronal injury observed with TBI [2,3] .

Preliminary research has shown potential neuroprotection after the intravenous injection of adult tissue progenitor or stem cells after TBI. By definition, adult tissue progenitor cells have the capacity for self-renewal and are multipotent (able to differentiate down multiple cell lines) [4] . Progenitor cells are maintained in select microenvironments throughout the body, which include bone marrow, adipose tissue, umbilical cord blood and within neural tissue (dentate gyrus and hippocampus). Within such niches, progenitor cell depletion, proliferation and activation are tightly regulated [5] .

Early preclinical work has shown functional improvement after the intravenous injection of bone marrow-derived mesenchymal stromal cells (MSCs) for the treatment of TBI. Many such studies hypothesized that the transplanted MSCs were engrafting at the site of injury and adopting neuronal cell markers indicating differentiation into neurons [6] . However, the role of 'transdifferentiation'â is now largely disregarded. Much debate remains about both the frequency and clinical significance as well as the validity of neural marker expression with most investigators believing this to be erroneous [7-9] .

A more recent hypothesis to explain the observed neuroprotection is progenitor cell engraftment at the site of injury with modulation of the locoregional inflammatory response. Work completed in the Cox laboratory has detailed the proinflammatory mircroenvironment of both the direct injury and penumbral regions of the brain after TBI, highlighting a potential target for progenitor cell therapy [10] . Additional in vitro studies investigating direct contact cultures of MSCs and immunologic cells have shown a decrease in proinflammatory cytokine production (IFN-γγ) with a concordant increase in anti-inflammatory cytokine production (IL-4 and -10) [11] . Unfortunately, results have been inconsistent with in vivo models. Such inconsistency is potentially secondary to limited progenitor cell engraftment and the pulmonary first pass effect.

Classic biodistribution studies that track MSCs after intravenous injection demonstrate that the overwhelming majority of cells are sequestered in the lungs [12] . Harting et al. demonstrated in a rodent TBI model that only 0.001% of intravenously transplanted cells engraft in the brain parenchyma with significant sequestration within the lung parenchyma (>96%) when evaluated 2-3 days after TBI. Furthermore, virtually no MSCs were found to remain in the parenchyma 2 weeks after transplantation [13] . Additional work completed in the Prockop laboratory has shown similar results with less than 0.001% of transplanted MSCs bypassing the pulmonary microvasculature [14] . Therefore, the observed pulmonary first-pass effect limits the number of MSCs that come into contact with the area of...

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Gale Document Number: GALE|A268609817