Episode Transcript
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This is the Discovery Files podcastfrom the U.S.
National Science Foundation.
Truly groundbreaking
research in health care is occurringall across the country, transforming
how we approach tissue repair, diseasetreatment and organ replacement.
Regenerative medicine focuseson repairing, replacing, or regenerating
human cells, tissues,or organs to restore normal function.
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We’re joined by Maksim Plikus,a professor of developmental
and cell biologyat University of California, Irvine,
where his lab studiesthe mechanisms of cell regeneration.
Professor Plikus,thank you so much for joining us today.
Thank you for having me on your show.
So I think we need to startwith a little definition as we move
into this topic and for people that don’tknow, what is regenerative medicine?
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So regenerative medicine,at least in my interpretation,
is an aspect of medicinethat relies on innate
ability of our tissuesto repair themselves and decimate.
Abilitiesare then harnessed for the benefit
of producing,for instance, new replacement tissues
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that in the deceased or tissueslost to injury could be substituted.
So thinking about the approachingregrowing human tissues,
how do you do that?
Obviouslymany people are thinking about it.
Many people are workingreally actively on it.
I think it’s one of the really fastevolving fields with huge potential.
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So I think a lot of hopes are thatit will work the way we scientists promise
it. Well, I think everything is quitedepends on context.
Right.
So I think, first questionone would want to ask
is what is the problemthat needs to be fixed?
And actually depending on a problem,regenerative medicine
solution would actually differquite a bit.
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If, for example, there is a catastrophic
loss of skin such as to a burn,then what one would want to do
is to completely replace the lost skin.
We already right now are able to produce
skin substitutesthat burn victims could be grafted to it.
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But when you look at the what we’reable to do right now and you compare it
to our actual skin, you quicklyrealize it’s really simplistic.
It lacks a lot of components thatnormal skin has that makes it what it is.
So I think the best outcome of use of skinsubstitutes is a tissue
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that looks a lot more like scarand a lot less like normal skin.
So we need to build much more intricatesubstitutes
that contain hair folliclesso your hair can grow, or sweat glands
so that can substitute could later sweatand help us in thermoregulation.
So we understand that our abilitiesto build super complex tissues
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that match those that we normally haveis still quite limited.
And then, of course, there are otherapplications for regenerative medicine.
I think a really classic example is typeone diabetes, where
patients lack insulinproducing beta cells in the pancreas.
So clearly if something is lackingyou can just put it back.
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So why don’t we make many more insulinproducing
beta cells and transplant it, shouldn’tthat work.
And in principle,it sounds like it should.
But the nature of the diseaseis autoimmune.
So your own immune systemwill go after transplanted
beta cells and kill them offagain and again and again.
So then it turns out that the regenerativemedicine solution for diabetes
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is a little bit more than justtransplanting cells or tissues, it’s
also protecting themfrom your own immune system.
So and I think one could really gointo a list of examples
where all these details matter.
So much for the success of the therapyonce it's ready.
Thinking about your research here,that we’re then to be talking about a bit
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what is lipo cartilageand where do you find it
in the body?You know, this name
really encapsulates what it is.
It’s a lipid filled cartilage tissue.
So it’s it’s really fatty skeletal tissue.
If you want me to put it that way.Where it’s found?
That’s a good question. It’snot found everywhere.
And not every single cartilage in our bodyis full of fat.
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It’s in our facial structuresand neck structures.
So cartilage in our earlobes,or cartilage in the tip of our nose.
Also cartilages that make up our larynx.
That’s where you find lipocartilages.
They’reso different from a typical cartilage.
It’s right.
So in a typical cartilagesdo not contain lipid in these cells.
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They just containa lot of extracellular matrix.
So this is, you know, proteinacioussubstance outside of the tissue.
So many questions then arise.
Why is the lipid in the cartiligesin our ear and nose and larynx?
What is it doing there?Is there a benefit to it?
What’s so special about it? Lipids.
So this list of questionscan really go on.
So what research were you doingor what question were you trying to answer
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when you guys found this? You know,it was quite simple.
We identified somewhat an abstract , okay.
And we were a little bit puzzled by itbecause we were looking
at pieces of skinthat should have adipocytes.
So adipocytes, you know, for our audience,our obviously fat filled cells,
but very different. Right.
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The ones that make up our fat tissues,
they look in a very certain wayunder the microscope.
So you can envision them.
They look like a really beautiful pearlthat is iridescent.
Once light shines on it.
Like it just like reallyhas this like, iridescent look to it.
Very pretty and very big.
So then we were looking at the smallpieces of tissue coming from a mouse ear.
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We’re looking at the adipocytes and we’refinding them.
So there is all this iridescentcells there.
But once we start studying themfor markers, we kind of realize,
wait a second.
Only a small portion of the cellslabeled with markers of adipocytes
and the larger portion,
even though they look exactlylike adipocytes, they don’t label.
So first I was like,we must be looking at rather very unusual,
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maybe different type of adipocyte.
And then as we starteddigging a little bit more and more,
trying to define this adipocytes,we came to this realization.
Wait a second,these are not adipocytes at all.
These are actually cartilage cells thatmasquerade themselves as an adipocyte.
They look like adipocytes, but molecularlythey’re completely different.
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And at that point, when it sort of,kind of hit us, we realize,
oh, we are dealingwith a distinct skeletal tissue
lipid filled cartilage and at that pointwere really put into high gear
trying to learn more.Was that an exciting finding for you guys?
Like why did thisgo overlooked for so long?
It was kind of super exciting.
You know,you could imagine it’s pretty rare in 2025
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to stumble upon a cell that nobody elsehad seen before described.
Right?
So you immediatelystart to question yourself like,
wait a second, I’mjust not know, something very obvious.
And if you ask experts in cartilage,they’ll say like, oh, come on, of course,
you know, like I’m
missing something in you should go backto your medical textbooks and read them.
Right.
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So we did that.
So we just couldn’tbelieve that nobody else saw them before.
And lo and behold, people did.
And the first personwho actually described
this cells in the ear cartilage of a rat
was this really well known scientistand contemporary of Charles Darwin.
His name is Franz Leydig.
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So he worked in what is now
Germany in middle 19th century.
So in 1854 he first described it
in his bookI don’t remember, like the exact word
to word translation of,you know, his description in German.
He drew it, by the way, so we knew, okay,he was looking at the same thing.
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But basically it said, when you’relooking at the cells under the microscope,
you’dthink you’re looking at adipocytes, cells.
But you know that this cannot bebecause what we put under
the microscope was cartilage.
So does we must be dealing with fat cells.
Cartilages. Case closed. Moved on.
I think he moved on to other things.
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And the rest of his book is just likea wild exploration of everything
that he could potentially findand put under the microscope.
So contemporary CharlesDarwin already found it.
And then for almost like 100 years,nobody seemed to have looked back
and realized that there is this cartilagethat has all this lipid in it.
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And then in the 1970s,there was a few descriptive papers
when electron microscopes becameactually fairly affordable and people
started sticking all kinds of stuffunder electron microscopes now.
And sure enough, somebody put earand sure enough, they realized
that, oh, there’s this very beautifullipid vacuoles in the cartilage.
Les described it. And so they did.
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And people working at that timewere also quite diligent
because they went back and they dug outFranz Leydig’s original description.
They know they gave it credit to it.
And then in like early 90s,
all of a sudden nobody’stalking about it again.
So we essentially where a third waveof rediscovery but now, you know,
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to our advantage we have all thismolecular tools and methods available.
So then we, you know, other thanjust like describing how they look,
we start studying the molecular biology,the physiology.
And as we were doing that,we realized that there’s so many unique
aspects about this tissueand about the cells you know.
We still know very little, but,
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therefore, we’re actually super excitedbecause of what’s possible.
What’s laying ahead.
So thinking about those possibilitiesa little bit, does the lipocartilage
cell lend itself towardsregenerative medicine potential usage?
I would argue that yes,there are many instances
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where cartilages of our face and neck
need to be replaced because, for example,
they are poorly developed due to birth
defects, birth defects of earlobes,actually really common.
Trauma of the ears, faceand neck is common.
There are certain forms of cancerthat could
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locally invadeinto like structures of the nose and neck,
and to save a patient’slife, that needs to be all cut out.
And Surgeon would have to removelarge portions of this cartilage.
And then what you’re having at that pointis big defect in the face or neck.
This all calls for replacement strategies.
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And of course there’s a category of,you know, elective plastic surgeries
where it might be beneficialto produce new cartilage
because, you know, it’s likenasal augmentation and things like that.
So then the question is like, okay, well,
where do you source this type ofcartilage? Turns out, cartilage
is one of those
tissues that if you talkingabout autologous cartilage,
you can cut pieces of the rib cartilage.
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And then shave itand then place it for example
into the tip of the nose or the ear,just like touching your rib.
You know, it’s not a soft right.
You can touch your earand see how to supply an elastic
and bouncy it feels and then touch the ribright and it’s totally different.
So biomechanics of tissuesare not the same.
So you’renot really doing 1 to 1 replacement.
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And on top of it cutting out cartilage ofthe rib is on it’s own and very invasive.
It’s not a joke.
You know, try to do something like thisand then any substitutes you know
people will also think, okaywell can we go to synthetic materials.
Can we replace cartilage with, say,silicone implants?
And yes, you can put a silicone implant,but silicone is a foreign body.
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And our body knows thatthis is a foreign body.
And it will tryreally, really hard to reject it.
It will form a capsule around it.
So longevity of this synthetic implantsis actually not very high.
So there needs to be a new solution.
You know I think one solutionthat we envision can regenerate
a lot of face and neck specific cartilage,which is lipocartilage from, let’s
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just say, pluripotent
stem cells in large numbersand then shape these cells into tissues
that match exactly what we’reaiming to produce.
And that would be is this worksreally a regenerative medicine solution.
Would make a lot of difference
for a lot of people that are sufferingfrom those kind of issues.
I would agree with that.
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I would like to pull out a little bitand look at the kind
of regenerative medicine field in general,like I think
last year I heard a story about being ableto regrow teeth a little bit.
What kind of things can activelybe regrown at this point in time?
I teach a class to my undergraduatescalled Advances in Regenerative Medicine,
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and every year I feel likeI have to go back and change something
that has over a year span of time,things have advanced dramatically, right?
Often, oftentimes
there is just new researchthat came out and months before
I have to start teaching in class.
That would completely change the lecture,because what I taught
last yearis all of a sudden out of date. right?
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And that really meansthat this is such a fast evolving field.
Almost every month theresome new discoveries,
some new advances in regenerative medicinethat have been reported.
So it’s really exciting.
And at the same time,like it’s really hard to stay current,
but a lot of understandinghas now exists of
what can we do at this point in timeand what else
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we need to learn to do to really translateold is very promising stem
cell based approaches into real therapiesthat could help people.
And I think that turns outto be a multifaceted problem.
There’s a lot of thingsthat we still need to learn.
So many questionsthat we still need to get answers to.
Can we make cartilage cells?Can we make chondrocytes?
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Can we make skin cells, keratinocytesand on and on.
Right.
I think the answer tothose questions is yes, we’ve learned.
So there are essentiallymolecular recipes.
When we culture cells, we can direct themtoward these outcomes that we desire.
At the end of it though, what we haveis really a suspension of cells.
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But our tissues are, forthe most part are not suspension.
So thereare essentially molecular recipes.
When we culture cells, we can direct themtoward these outcomes that we desire.
At the end of it though, what we haveis really a suspension of cells.
But our tissues are, forthe most part are not suspension.
How do you regenerate tissuesthat are not just tiny microscopic?
We need a magnifying glass to see them.
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How do you make them big?
Because we’re a fairly large organism.
So how do we make somethingthat's like ten by ten centimeters..
So how do we make somethingthat’s like ten by ten centimeters.
And that turns out theseare the challenges, the scaling of things,
the micro patterning of things.
It’s still often wewe don’t really know how to go about it.
But a lot of research is in this area.
So thinking about research,I want to ask you about
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how NSF support has impacted your careerso far?
NSF support was absolutely,fundamentally essential for us to be able
to think outside of the boxand feel like we can support our efforts,
because at the point in time,when I mentioned in my earlier answer,
when we were looking at adipocytes,because, you know,
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the project that we were working onwas adipocytes.
And the point in timewhen we realized that, oh,
this iridescent pearl lookingcells, actually chondracytes, there’s
some kind of interesting cartilagethat nobody knows anything about.
We could have said, okay, well, then it’snot fitting into what we’re working on.
Let’s let’s move on. Let’sput it to the side.
It’s it’s not our business. Right.
But instead, it really peakedour curiosity and we decided, no, we’ll
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throw everything in the kitchensink at it.
We’re going to figure out what this is.
So it was in many ways just this ability
to do researchin a completely new direction.
So for my last question today,I want to ask you, circling back
to the lipocartilage,and I want to ask you about what’s next.
What are you excited to learn about itin the next couple of years?
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Many things, but amongst thoseso many things is biomechanics.
I think that’s really interesting
because skeletal tissueis about biomechanics, right.
But our bones, our cartilages,they provide our body’s support.
And then when we, meaning scientiststypically think about
biomechanics of cartilages
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almost alwayswe think about molecular properties
of the extracellular matrix,like things such as collagen.
You know how does bendable molecules
endow cartilage with its properties,such as elasticity, stiffness.
But now in lipo cartilage, there’svery little of this extracellular matrix.
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And instead there are very largecells filled with lipid droplets.
So then the question that we really,really want to get the answer to is
what is the role of intracellularlipid droplets in tissue biomechanics?
We already have cluessuggesting that they play a central role.
That really suggeststhat the lipo cartilage biomechanics,
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they’rea composite material made by nature.
It’s the intracellular lipid dropletsworking together
with extracellular matrix proteins,producing this composite tissue
with biomechanical propertiesderive at this like synergy point.
And so trying to learn thatis that what we really want to do next.
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Special thanks to Maksim Plikus,for The Discovery Files, I’m Nate Pottker.
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