Transplanted human brain-tissue takes root in mice without a cortex

Benjamin Thompson (0:04)

Nature, I don't know yet, why it's like so far?

James Zou (0:08)

Like it sounds so simple, they had no idea.

Aparna Bhaduri (0:10)

But now the data's...

Benjamin Thompson (0:24)

Welcome back to The Nature Podcast. This week, transplanting human brain organoids into mice and how to turn a scientific paper into an AI you can talk to.

Nick Howe (0:36)

I'm Nick Patrick-Howe.

Benjamin Thompson (0:37)

And I'm Benjamin Thompson.

First up this week, we hear how researchers have transplanted human brain-like tissue into mice and watched it grow and develop, a technique they hope will aid in the future understanding of brain development or disease. Now, one of the ways that scientists have been studying the complexities of the human brain is by using organoids. Derived from human stem cells, these small 3D clumps of brain-like tissue are grown in a dish, either individually or combined into more complex structures called assembloids. But while these systems have transformed the way that researchers study developmental processes or disease progression, their in-vitro nature means they may not be able to mimic some of the specifics of brain function, meaning they may not be applicable for use in every situation.

Sergio Pasca (1:41)

Even in these preparations that can be kept for like years in a dish, we realize that there are a number of aspects that kind of prevent their full potential.

Benjamin Thompson (1:50)

This is Sergio Pacheca from Stanford University in the US.

Sergio Pasca (1:54)

One of them is quite interestingly, the fact that cells can sit in a dish, but there are no physiological inputs and there are no outputs. And we know that those are really important for the brain to truly develop.

Benjamin Thompson (2:05)

Back in 2022, Sergio and his colleagues looked to get around this by implanting a human brain organoid into the brain of a newborn rat. He spoke to us on the podcast about it at the time. This method is something he and others have been using in their research, but it too has some limitations. Namely, that human brain cells grow a lot slower than rodent brain cells, and essentially the implanted organoid gets outcompeted, losing the chance to make connections and the space it needs to grow.

Now Sergio and his colleagues have looked to overcome this issue with a different approach, and they have a paper out about it in Nature This Week.

Sergio Pasca (2:43)

And so the idea was like, could we actually create a strategy that would allow us to create some of like this space? And could we actually do it in a clean, precise way? So we thought that the best way would be not to do it surgically, but to actually do it genetically.

Benjamin Thompson (2:58)

And this is what they've done, working in mice this time, using a genetic approach to prevent part of the animal brains from growing.

Sergio Pasca (3:05)

So we removed parts of the nervous system that is called the pallium. So this is a structure that is present, you know, early in development, and will give rise to the cerebral cortex, the outer layer of the brain, the hypercampus, which is very important for memory.

And so what we essentially did here is use the strategy that allows us to delete a gene that is very important for cells to divide, but only in the cells that are going to form this brain regions in development. So in other words, the moment the cells are actually born and they're ready to make a cortex, they can divide. So they're just stuck there and very few early cells.

Benjamin Thompson (3:46)

Despite losing almost half of their brain volume through the loss of their palliums, these apaleol mice survive. And although they show reduced body weight compared with control mice, they were broadly similar in terms of basic mobility and sensory responses.

The team then transplanted human stem cell-derived cortical organoids into newborn apaleol pups that were between 5 and 17 days old, and watched the cells develop.

Sergio Pasca (4:14)

We essentially place about 4 cortical organoids in that vacant space. Each of them has probably 100,000 cells or so. So they're not a lot of cells. They already have been differentiated so that they're going to make cortical cells. So they're on that path to form cortex. And essentially, we just place them in, and that's it, through one single injection.

So it turns out that the human cells, they will divide and they will start differentiating. They're going to become vasterized by the host. Immune cells from the mouse are actually going to move inside the human graft.

Benjamin Thompson (4:49)

Over the course of a few months, the organoid cells divided to take up empty space.