Errata
Terlipressin-More than just a prodrug of lysine vasopressin?: Erratum
In the article on page 1135, the last author’s name was inverted. It should have been: Andrea Morelli
Critical Care Medicine.
37(5):1836,
May 2009.
In this issue of Critical Care Medicine, Jiang et al (1) provide the first report describing a stem cell-based strategy for ameliorating brain injury after carbon monoxide (CO) poisoning. By using a rat model, the authors demonstrated that infusing bone marrow-derived stem cells 24 hours after poisoning could diminish CO-induced learning impairment assessed by Morris Water maze tests at 5 weeks postpoisoning, and they also showed that treatments improved brain histology. Benefits followed infusion of bone marrow-derived stem cells into the carotid artery, and somewhat better results were found using bone marrow cells that had been cultured for a period of time ex vivo to induce them to differentiate toward a neuronal stem cell phenotype (MS-NSCs). Infused stem cells were diffusely distributed and could be found in brain areas know to be injured by CO, including the cerebral cortex, hippocampus, basal ganglia, and subventricular white matter.
This is an exciting and provocative investigation on many levels. The major conclusion in the article is that infused stem cells are sequestered in the injured brain and these cells seem to mediate improvements of neurologic function. The authors suggest that MS-NSCs transplants exhibit higher survival rates and terminal neurocyte differentiation vs. bone marrow-derived stem cells. Because the number of transplanted cells is relatively small, they believe that paracrine effects occur wherein the stem cells liberate agents or growth factors that improve function of endogenous brain cells. These ideas are well supported in the literature and there are also alternative possibilities.
Stem cell-based therapies have shown promise for treating acute hypoxic–ischemic injuries (e.g., stroke), chronic neurodegenerative diseases (e.g., Parkinson’s disease), inflammatory disorders (e.g., multiple sclerosis), and even some inborn errors of metabolism (2). CO-mediated brain injury does not fit into a single pathophysiologic category. Animal studies indicate that CO poisoning initiates a progressive neuropathologic process with overlapping elements of hypoxic–ischemic, excitotoxic, and immune-mediated brain injury (3–6). Therefore, looking at a treatment that supports the injured brain tissue without the need to address primary pathologic mechanisms is attractive.
Numerous approaches have been taken to treat neurologic diseases with stem cells (2). Neural stem and progenitor cell types, embryonic stem cells, umbilical cord, and also bone marrow-derived stem cells have been harvested and sometimes grown ex vivo. They have been delivered by direct injection into brain parenchyma, into the subarachnoid, or the cerebroventricular spaces, or infused by intravenous or intra-arterial routes. Allogeneic approaches are effective, and some studies have shown that autologous cells obtained from an individual’s own bone marrow can be effective. Thus, some success was reported using endogenous bone marrow-derived cells mobilized by cytokines and growth factors (7). Stem cell homing to injured tissues occurs, but the mechanism(s) remain unclear. Stem cells are thought to respond to proteins expressed by injured neurons or other cell types located in the injured brain (2).
No matter the source or route of administration, stem cells rarely differentiate and replace missing neurons. Rather, stem cells seem to provide trophic support to injured brain tissue by local synthesis of neurotrophins or other growth factors, by stimulating remyelination, by enhancing axonal regeneration because stem cells synthesize a supportive extracellular matrix, or because stem cells produce metalloproteinases that ease passage of regenerating axons through glial scars (8–10). Particularly, with rodent models of stroke, coupling between angiogenesis and neurogenesis can be shown. Stem cell-mediated angiogenesis leads to preservation of neurons and improved functional outcome. In some models of inflammatory brain injury, intravenously administered neural progenitors or bone marrow stromal cells exhibit immunosuppressive effects by interacting with T cells, and this reduces brain inflammation and disease severity (11, 12). Obviously, the exact mechanisms involved with ameliorating CO-mediated brain injury are unclear and will require further study.
To date, the only treatment shown to improve neurologic outcomes after CO poisoning in clinical trials is hyperbaric oxygen and intervention within the first 24 hours is likely to be critical (13). In the animal model used by Jiang et al, hyperbaric oxygen was shown to be beneficial, but intervention at times latter than 90 minutes postpoisoning has not been examined (14). Thus, stem cell-based therapy may offer a more flexible treatment option with a broader therapeutic window of opportunity. Ironically, recent evidence suggests that some of the same mechanisms linked to stem cell-based therapies are triggered by hyperbaric oxygen, as this treatment will abate the acute CO-mediated inflammatory process and hyperoxia mobilizes bone marrow-derived stem cells (15–17).
Stephen Thom, MD, PhD
Department of Emergency Medicine
University of Pennsylvania
Philadelphia, PA
Critical Care Medicine.
37(4):1520-1521,
April 2009.
Structural and functional improvement of injured brain after severe acute carbon monoxide poisoning by stem cell-based therapy in rats: Erratum
In the article on page 1416, some of the affiliations were incorrect. They should have been:
From the Emergency Center (Guoping Jiang, YX, YM, Guanyu Jiang), Clinical Research Centre (WY) of The Second Affiliated Hospital, and Critical Care Department (JG) of The Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Critical Care Medicine.
37(5):1836,
May 2009.