Aerobic glycolysis, the method by which cells transform glucose into lactate, is essential for eye development in mammals, in line with a recent Northwestern Medicine study published in Nature Communications.

While it has been well-known that retinal cells use lactate during cell differentiation, the precise role that this process plays in early eye development was not previously understood.

The findings further the sphere’s understanding of the metabolic pathways underlying organ development, in line with Guillermo Oliver, PhD, the Thomas D. Spies Professor of Lymphatic Metabolism, Director of the Feinberg Cardiovascular and Renal Research Institute Center for Vascular and Developmental Biology, and senior creator of the study.

“For a very long time, my lab has been all in favour of developmental biology. Specifically, to characterize the molecular and cellular steps regulating early eye morphogenesis,” Oliver said. “For us, the query was: ‘How do these remarkable and important sensory organs we have now in our face begin to form?'”

Nozomu Takata, PhD, a postdoctoral fellow within the Oliver lab and first creator of the paper, initially approached this query by developing embryonic stem cell-derived eye organoids, that are organ-like tissues engineered in a petri dish. Intriguingly, he observed that early mouse eye progenitors display elevated glycolytic activity and production of lactate. After introducing a glycolysis inhibitor to the aesthetic organoids, normal optic vesicle development halted, in line with the study, but adding back lactate allowed the organoids to resume normal eye morphogenesis, or development.

Takata and his collaborators then compared those organoids to controls using genome-wide transcriptome and epigenetic evaluation using RNA and ChIP sequencing. They found that inhibiting glycolysis and adding lactate to the organoids regulated the expression of certain critical and evolutionary conserved genes required for early eye development.

To validate these findings, Takata deleted Glut1 and Ldha, genes known for regulating glucose transport and lactate production from developing retinas in mouse embryos. The deletion of those genes arrested normal glucose transport specifically within the eye-forming region, in line with the study.

“What we found was an ATP-independent role of the glycolytic pathway,” Takata said. “Lactate, which is a metabolite often called a waste product before, is actually doing something cool in eye morphogenesis. That actually tells us that this metabolite is a key player in organ morphogenesis and particularly, eye morphogenesis. I see this discovery as having broader implications, as likely also being required in other organs and possibly in regeneration and disease as well.”

Following this discovery, Takata said he plans to proceed to benefit from traditional and emerging developmental biology’s tools comparable to mouse genetics and stem cells-derived organoids to check the role of the glycolytic pathway and metabolism in the event of other organs.

The findings is also useful in higher understanding the direct effect that metabolites could have in regulating gene expression during organ regeneration and tumor development, Oliver said.

“Each regeneration and tumorigenesis involve developmental pathways that go awry in some occasions, or it’s worthwhile to reactivate,” Oliver said. “For a lot of developmental processes, you wish very strict transcriptional regulation. A gene is on or off at certain times, and when that goes incorrect, that could lead on to developmental defects or promote tumorigenesis. Now that we all know that there are specific metabolites chargeable for normal or abnormal gene regulation, this will broaden our considering on approaches to therapeutic treatments.” Additional Feinberg faculty co-authors include Ali Shilatifard, PhD, the Robert Francis Furchgott Professor and chair of Biochemistry and Molecular Genetics and director of the Simpson Querrey Institute for Epigenetics, Alexander Misharin, MD, PhD, associate professor of Medicine within the Division of Pulmonary and Critical Care, Jason M. Miska, PhD, assistant professor of Neurological Surgery and Navdeep Chandel, PhD, the David W. Cugell, MD, Professor of Medicine within the Division of Pulmonary and Critical Care and of Biochemistry and Molecular Genetics.

The study was supported by an Illumina Next Generation Sequencing award..