Astrocyte subtypes

I’m a neuropathologist at the DoD/USU Brain Tissue repository studying the neuropathology of blast-associated mTBI. Blast-exposed service members, especially those in the Special Forces, sometimes develop a neuropsychiatric syndrome similar to, but clearly different from PTSD, and often commit suicide. It is their brains that we are studying.

We have tentatively identified hypertrophy/hyperplasia of intralaminar astrocytes as important in the pathophysiology of these patients’ clinical disease and we will be collecting single nucleus (10x Genomics Chromium) data to further characterize the changes in these brains.

The original Allen Brain human cortical taxonomy (RNA-Seq Human Data Navigator :: Allen Brain Atlas: Cell Types) has two types of astrocytes which pretty clearly represent protoplasmic astrocytes and intralaminar astrocytes (possibly combined with the “varacose projection astrocytes”). The next taxonomy had three subtypes one of which might be an activated state of the intralaminar astrocyte, but that’s just a guess. But the SEA-AD webpage (Transcriptomics Explorer :: Allen Brain Atlas: Cell Types) has 5 subtypes and the SEA-AD taxonomy you presented now has six. I have absolutely no idea how to make biological sense out of that.

1> What can anyone tell me about the cell biology of these six astrocyte subtypes? If you’ve already solved this problem then that’s one wheel I won’t have to re-invent. But the only thing I can say now is that, based on CD44 expression, the intralaminar astrocyte is probably Astro_3.

2> Most importantly, who in the Allen Brain Institute has a special interest in astrocytes?

Thanks.

Harker

C. Harker Rhodes, MD, PhD
Professor of Pathology and Neurology (Retired)
Geisel School of Medicine at Dartmouth

Senior Neuropathologist [HJF contract employee]
DoD/USU Brain Tissue Repository
6720B Rockledge Drive, Lab 276
Bethesda, MD 20817

Dear Harker,

Thanks for reaching out. As you mention, we have several different classifications of human (and mouse) cell types, and navigating between them can be challenging. We’re working on ways to better link this knowledge together–stay tuned!

As for your actual question, a recent study comparing cell types across species (Comparative transcriptomics reveals human-specific cortical features - PMC) looked at astrocytes (among other cell types), and by combining information from figures 4 and S5 along with a plot from an upcoming tool, here is what we get:


It looks like Astro_4 and Astro_5 are intralaminar, while Astro_3 (and maybe Astro_1?) is fibrous. Astro 2 is protoplasmic. Finally, Astro_6_SEAAD is a type that was not present in this paper and represents a type found in an aged population with AD pathology (https://sea-ad.org/). I don’t have a good explanation for expression of CD44 in Astro_3, but that sounds like a good area to research!

As for who at the Allen Institute has special interest in astrocytes, I’ll let other folks chime in, but I do want to point to a recent preprint on gaining genetic access to astrocytes: Enhancer-AAVs allow genetic access to oligodendrocytes and diverse populations of astrocytes across species - PubMed.

Finally, I want to point you to our Aging, Dementia, and Traumatic Brain Injury Study: https://aging.brain-map.org/, in case you are unaware. This study looked at a matched set of aged donors with and without self-reported TBIs in their lifetime (so not the same cohort as what you are looking at, but still of potential interest). As part of this study we collected image data and quantitative image metrics to assess β-amyloid, tau, and α-synuclein pathologies as well as the overall local pathological state of tissue samples from each donor (which can be accessed here: Specimen Summary :: Allen Brain Atlas: Aging, Dementia and TBI Study).

Best,
Jeremy