Journal Club: Alport syndrome & the cochlea: Increase in Laminin α2 and thickening of lining surrounding small blood vessels.

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Today's journal article

Meehan DT, Brockhouse J, Connell K, Madison J, Gratton MA, Cosgrove D. Alpha-dystroglycan receptor signaling likely influences basement membrane laminin α2 mediated pathology in the stria vascularis of Alport mice. 

Why I picked this article

According to the Alport syndrome foundation, Alport syndrome is a rare genetic disease that causes kidney problems, hearing loss and vision problems. The reliable prevalence studies are available, with an estimated number of 200,000 in the USA (https://alportsyndrome.org/). In the inner ear organ of hearing, the cochlea, small blood vessels are affected in Alport syndrome; the membrane lining surrounding the small blood vessels are thickened, causing dysfunction of these small blood vessels and likely impacting cochlear function. 

Alport syndrome is caused by variants in genes called COL4A5, COL4A3 and COL4A4, all blueprint for a protein called collagen type IV (https://www.ncbi.nlm.nih.gov/books/NBK470419/). This research investigates how variants in collagen type IV genes can cause thickening of the walls of small blood vessels. They have focused on two proteins, "α-dystroglycan receptor" and "Endothelin-1". The former is a type of protein called a receptor, and can bind to laminin α2. Laminin α2 is a protein that constitutes the lining surrounding the blood vessel. The latter, endothelin 1 or ET-1 is a protein that is known to shrink the diameter of small blood vessels. 

Some of the research findings

Experimental Model:

  • Alport syndrome model mice: 129 Sv autosomal Alport mice (COL4A3 -/-) developed previously in Cogrove lab
  • Cochlear cell culture: stria vascularis, an area of the cochlea rich in small blood vessels, was dissected, and cells were cultured from the tissue to isolate two different clones. 
  • Clone 34 was designated as "intermediate cell-like" based on the proteins it contained.
  • Clone 39 was designated as "marginal cell-like"
  • Pericyte cells: pericytes are special cells that regulate blood flow in small blood vessels. Pericyte cells were from Dr Xiaouri Shi's lab.
Findings:
  • Alport syndrome model mice developed thickening of the lining surrounding small blood vessels, as expected, in the cochlea. 
  • The target proteins of this research, α-dystroglycan receptor, were found to be present in blood-vessel-rich areas of the cochlea and in cultured cells. 
  • The amount of Laminin α2, the protein in the lining surrounding small blood vessels, was much more increased in the Alport syndrome model mouse cochlea. 

Part of Figure 4A, Meehan (2025). Small blood vessels in the cochlea. Red labels the α-dystroglycan, green is blood vessel cells, and blue is the cell nucleus. 

  • When cochleae from normal and alport syndrome model mice were compared using a technique "RNA-seq", there was a very little difference between the two groups, except for some proteins (e.g. Integrin α11, laminin α1, ankyrin repeat). These proteins are typically important for holding cells and structures together. 
  • When pericytes cultured from the cochlea were treated with "Endothelin-1 (ET-1)" for 45 minutes, modifications happened to the protein "actin", and also to a group of proteins that regulate the cell cycle. This was also demonstrated by the microscopy. 

Taken together, this research has identified multiple proteins that may regulate blood flow in the small blood vessels of the cochlea, with the potential implication that they may be the primary cause of pathologies in Alport syndrome. 

Haruna's takeaway

Another systemic, genetic condition that affects both eyes and ears! In the case of Alport syndrome, the kidneys are also affected. What is common is the fact that the kidney, the eye and the cochlea have highly protected small blood vessels. Pericytes are very important in both eyes and the cochlea. 

I found the culturing methodologies in this publication to be very interesting. I wonder how easy/difficult it is to say extract some cells (i.e. fibrocytes) or cells of blood vessels from the human inner ear; the cochlea may not be very hard to have an opportunity, however, isolating cells from the human vestibular system during an operation for vestibular schuwannoma has been successfully done. There are advantages to establishing a cell line to fully understand protein functions. 

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This is Haruna's 22/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.