2019 Alston Callahan, MD Postdoctoral Scholar Recipient

Akshayalakshmi Sridhar, PhD

University of Washington
Seattle, Washington

Project title: Building fovea-like retinal organoids from human pluripotent stem cells.

During her first year as a postdoctoral fellow at University of Washington’s School of Medicine, Dr. Sridhar has garnered ‘attention as a rising star,’ according to Dr. Thomas Reh.  “Dr. Sridhar is exceptionally motivated and very bright. She has only been in my lab for just over one year, but has already made great progress on several projects involving retinal organoids,” says Reh.  He went on to explain that Dr. Sridhar applied to his lab to further develop her knowledge of neural retinal development and to develop the retinal organoid system to fully reflect normal fetal human embryogenesis, which he describes as an ambitious goal.

The goal of Dr. Sridhar’s proposal is to build fovea-like organoids from human pluripotent stem cells (hPSCs).  Sridhar explained that given their pluripotent nature, hPSCs serve as a unique and novel tool to allow access to early stages of retinal development.

Dr. Sridhar is joint first author, along with Thomas A. Reh and Akina Hoshino, on a paper recently published, which demonstrates for the first time that the epigenetic aging clock already tracks chronological age in fetal tissue and organoids.  She is also preparing two additional manuscripts on single cell RNAseq analysis of fetal human retina and retinal organoids. “This is a remarkable accomplishment,” comments Dr. Reh, “typically it takes several years for a new postdoctoral fellow to submit a single report for publication, yet Dr. Sridhar already has most of the data for three publications.”

Synchrony and asynchrony between an epigenetic clock and developmental timing.  Akina Hoshino1, Steve Horvath2, Akshayalakshmi Sridhar1, Alex Chitsazan3, & Thomas A. Reh1

1Department of Biological Structure, University of Washington, Seattle, WA, 98195, USA.  2Human Genetics and Biostatistics, David Geffen School of Medicine, University of California Los Angeles, Gonda Research Center, Los Angeles, CA, 90095-7088, UAS.  3Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.

ABSTRACT: Epigenetic changes have been used to estimate chronological age across the lifespan, and some studies suggest that epigenetic “aging” clocks may already operate in developing tissue.  To better understand the relationship between developmental stage and epigenetic age, we utilized the highly regular sequence of development found in the mammalian neural retina and a well-established epigenetic aging clock based on DNA methylation.  The results demonstrate that the epigenetic age of fetal retina is highly correlated with chronological age. Also established, epigenetic aging progresses normally in vitro, suggesting that epigenetic aging is a property of individual tissues.  This correlation is also retained in stem cell-derived retinal organoids, but is accelerated in individuals with Down syndrome, a progeroid-like condition.  Overall, the results suggest that epigenetic aging begins as early as a few weeks post-conception, in fetal tissues, and the mechanisms underlying the phenomenon of epigenetic aging might be studied in developing organs.

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