Stanford: Brain Progenitor Cells Discovery Uncovers Distinct Origins

• Stanford Medicine researchers discovered that the front and back of the brain develop from entirely different progenitor cells, challenging previous scientific understanding.
• This breakthrough allows for the first-time growth of functional human hindbrain motor neurons in a laboratory setting from pluripotent stem cells.
• The hindbrain, which controls vital automatic functions and muscles for speaking and swallowing, is affected by diseases like ALS and SMA.
• The new lab model is crucial for studying these devastating neurological conditions, as brain stem tissue cannot be obtained from living patients.
• Evolutionary analysis revealed this two-part brain development pattern in diverse species, suggesting an ancient origin for the brain's structure.

This finding, published on Friday in Nature Neuroscience, challenges a long-held scientific belief that the entire brain developed from a single type of progenitor cell.

A recent Stanford Medicine-led research effort has fundamentally reshaped the understanding of human brain development, revealing that the brain's anterior and posterior regions originate from entirely distinct progenitor cells. This finding, published on Friday in Nature Neuroscience, challenges a long-held scientific belief that the entire brain developed from a single type of progenitor cell.

According to Kyle Loh, an associate professor of developmental biology at Stanford Medicine and the study's senior author, this Stanford brain progenitor cells discovery means researchers can now cultivate hindbrain neurons in a laboratory setting, enabling unprecedented study of their functions. The breakthrough allows for the first-time growth of human hindbrain motor neurons from pluripotent stem cells, which then exhibited characteristic electrical activity and produced proteins associated with facial and swallowing muscle control.

For decades, the prevailing scientific consensus posited a singular cellular origin for the entire brain. However, the new research demonstrates that the front and back of the brain follow separate developmental trajectories from their inception. This divergence was traced back to gastrulation, a critical early stage of embryonic development where the body's basic form begins to take shape.

Through examinations of mouse embryos, the research team identified two distinct populations of brain progenitor cells. Cells expressing the Otx2 gene were found to develop into the forebrain and midbrain, while cells expressing the Gbx2 gene formed the hindbrain, with no observed overlap between these populations. Further analysis of chromatin, which dictates how DNA is packaged and gene accessibility, revealed different configurations in the two progenitor cell types, effectively committing them to their separate developmental paths. This explains why previous attempts to generate hindbrain neurons by trying to convert forebrain or midbrain progenitors were unsuccessful, as noted by graduate student and co-first author Rayyan Jokhai.

The ability to grow hindbrain neurons in a petri dish holds significant implications for understanding and treating devastating neurological conditions. The hindbrain, encompassing the brain stem, is crucial for essential automatic bodily functions such as breathing, sleep regulation, heartbeat, and hunger, in addition to controlling muscles vital for speaking and swallowing. Despite these critical roles, scientists have historically struggled to cultivate human hindbrain neurons in the lab, impeding research into diseases that damage them.

Conditions like spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) directly affect these vital hindbrain neurons. Since obtaining brain stem tissue from living patients is not feasible, laboratory models are indispensable for comprehending the mechanisms of neuronal damage in these diseases. This Stanford brain progenitor cells discovery provides a novel and crucial model to investigate SMA, ALS, and other brain stem-related disorders, paving the way for potential regenerative therapies, as highlighted by Jokhai.

The researchers also delved into evolutionary history, uncovering evidence of this two-part brain development pattern in a range of species, including chickens, zebrafish, and acorn worms, all of which share a distant common ancestor with humans. Intriguingly, jellyfish, which diverged from humans approximately 600 to 700 million years ago, possess two distinct nervous systems located at opposite ends of their bodies.

Kyle Loh suggested that evolution likely integrated two pre-existing neural systems spatially to form what we now recognize as a single brain. While a unified brain might appear more efficient, human brain development still relies on this ancient, two-part construction method. The next phase of research will focus on exploring the developmental origins of the spinal cord and how diseases such as SMA and ALS specifically impact hindbrain neurons.

Source: Original reporting via Courthouse News