Health,Stem Cells, and Technology

Saturday, June 25, 2016

Macrophages Mediate the Repair of Brain Vascular Rupture through Direct Physical Adhesion and Mechanical Traction


Highlights

  • Zebrafish brain vascular rupture and repair system is established
  • Live imaging reveals the dynamic cellular events of brain vascular repair
  • Macrophages mediate brain vascular repair through adhesion and mechanical traction
  • Macrophage-mediated brain vascular repair requires PI3K and Rac1 activity

Summary

Hemorrhagic stroke and brain microbleeds are caused by cerebrovascular ruptures. Fast repair of such ruptures is the most promising therapeutic approach. Due to a lack of high-resolution in vivo real-time studies, the dynamic cellular events involved in cerebrovascular repair remain unknown. Here, we have developed a cerebrovascular rupture system in zebrafish by using multi-photon laser, which generates a lesion with two endothelial ends. In vivo time-lapse imaging showed that a macrophage arrived at the lesion and extended filopodia or lamellipodia to physically adhere to both endothelial ends. This macrophage generated mechanical traction forces to pull the endothelial ends and facilitate their ligation, thus mediating the repair of the rupture. Both depolymerization of microfilaments and inhibition of phosphatidylinositide 3-kinase or Rac1 activity disrupted macrophage-endothelial adhesion and impaired cerebrovascular repair. Our study reveals a hitherto unexpected role for macrophages in mediating repair of cerebrovascular ruptures through direct physical adhesion and mechanical traction.

Sunday, June 19, 2016

Clinical Trial to Begin Targeting Vasculogenic Mimicry:

Tumors have been known for many years to grow their own blood supply, and this mechanism became a target for many cancer therapeutics (Folkman, 1971). In 1999, Dr. Andrew Maniotis, Ph.D., a colleague of Folkman at Harvard Medical School who had moved to the University of Iowa, discovered a different means by which tumors can supply themselves blood and nutrients. The mechansim was named vasculogenic mimicry (VM) because the extracellular matrix and microenvironment surrounding the tumor had transformed into an architecture that included channels resembling the vasculature (Maniotis et al, 1999).

 This year a company launched a phase I trial to evaluate the safety of CVM-1118 in people with a variety of untreatable cancers and to assess its effectiveness. The new drug CVM-1118 curbs the activity of Nodal, a gene that drives vasculogenic mimicry by making cancer cells more like stem cells. While this new therapeutic strategy uses the advantage of knocking down one important pathway in the development of VM, cancer is a biological entity, and as such, usually has a variety of adaptive strategies available to circumvent this "one pathway disruption" caused by CVM-1118. Many other "one molecule for one pathway" strategies to treat cancer have failed in the past. We'll know soon whether CVM-1118 joins the ranks of the many drugs that do little or nothing to treat cancer.

References:

Judah Folkman (1971) Tumor Angiogenesis: Therapeutic Implications. N Engl J Med 1971; 285:1182-1186November 18, 1971DOI: 10.1056/NEJM197111182852108

Maniotis AJ1, Folberg R, Hess A, Seftor EA, Gardner LM, Pe'er J, Trent JM, Meltzer PS, Hendrix MJ. (1999) Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol. 1999 Sep;155(3):739-52.

Saturday, June 4, 2016

Colloidal Silver: Inhaled silver particles end up in the brain


Airborne silver nanoparticles that are common in occupational settings travel from the nose to the brain, where they can remain for weeks and trigger an immune response linked with injury, UC Davis researchers studying adult rats have found.

Author of the study, Dr Kent Pinkerton, Ph.D. at UC Davis, published in the journal Environmental Health Perspectives, urge greater attention to the health effects of silver nanoparticle exposure, given the increasing likelihood of exposure and how little is known about the risks to the central nervous system.

His team exposed adult male rats to a single dose of aerosolized silver nanoparticles measuring 20 or 110 nanometers (or one billionth of a meter) in diameter. The team used levels similar to what a human would receive after one day of light work in an occupation, such as manufacturing, where the nanoparticles would be present.

After evaluating the animals over the course of eight weeks, they found that particles of both sizes migrated through olfactory epithelial nerves into an area of the forebrain called the olfactory bulb.

While it was not much of a surprise that the 20nm particles reached the olfactory bulb, the 110nm particles were a different story. It should be physically impossible for this size to move through the olfactory epithelial nerves.

Almost immediately after being exposed to the nanoparticles, especially smaller ones, the team saw an activation of microglial cells in the brain. Microglial cells are a type of macrophage and are associated with free radical generation, indicating the possibility of central nervous system damage when activated.

Something to consider is the widespread use of colloidal silver, a suspension of silver nanoparticles.