Stem Cell Bioengineering
for Generation of Tissues and Organs

Brenda M. Ogle, PhD
Assistant Professor
Department of Biomedical Engineering
University of Wisconsin-Madison
8/18/2006

00:00
Hello, my name is Brenda Ogle. 
I'm an Assistant Professor in the Department of 
Biomedical Engineering here at the University of Wisconsin in Madison.
Today, I'm going to share with you a bit 
about our laboratory and the research ongoing 
related to stem cell bioengineering 
for the generation of tissues and organs.

00:24
My academic background began in mathematics and mechanical engineering, 
and I obtained my PhD from the University of Minnesota in the Twin Cities 
in the Department of Biomedical Engineering. 
There, my research thesis was related to the enhancement 
of the mechanical properties of a tissue-engineered blood vessel.

00:46
I later went on to the Mayo Clinic to conduct post-doctoral studies. 
These studies were related to enhancing or reconstituting the immune system 
in those who suffer defects in the system, 
for example, those with HIV, 
those who've undergone anticancer therapies. 
Those studies are ongoing, and I'll describe them in a few minutes.
I've also had several internships in medical device companies 
in Minneapolis, including Augustine Medical and Medtronic.

01:20
The research in our group can be broken down 
into the four general categories that I've identified here.
The first item, or research item that we attempt, 
is to identify conditions in which stem cells are induced 
to commit or differentiate to a particular cell type. 
We also seek to manipulate these conditions in vitro and in vivo 
to develop cell sources for tissue and organ regeneration. We also have an animal model that we utilize to develop in vivo organs. 
And, finally, we seek to characterize and optimize 
the mechanical properties of all tissues that we generate 
in culture and in vivo. 
I've placed a gold cross next to those activities that are translational in nature.

02:08
The motivation for the work that we conduct is driven 
by some of the limitations that have recently been discovered 
in stem cell therapies. 
For example, it was thought not too long ago that perhaps 
the transplantation of stem cells could serve 
to repair myocardial infarction or myocardial ischemia. 
And that actually took place in studies in mice and rodents 
where stem cells were in fact injected into injured myocardium, 
and it was found as shown in the histological cross-sections here, 
that with stem cell transplantation, cardiomyocytes could be derived 
and did in fact increase the functional capacity of the heart. 
Unfortunately, in clinical studies such as the one I'm showing here 
by Janssens in the Lancet, clinical results have been less than exciting; 
in fact, if you look at function in terms of left ventricular ejection fraction, 
there is no difference between the treated and the control groups.

03:10
We're also motivated by a model system we've developed recently 
for regeneration of tissues. 
We first developed the model to determine whether or not human T cells could develop in surrogate animals.
To do this, I extracted human hematopoietic stems cells 
from either bone marrow or cord blood, injected them into fetal animals, 
in this case, fetal pigs, injected them at a time during gestation 
when the cell media to the immune response was not mature, 
and so that the graft could in fact be sustained, 
and then we looked at the progeny at birth and at several points 
after birth to determine whether or not human T cells had matured and were present. 
And the ultimate therapy being that those T cells could then be isolated 
from the pig and injected back into the original donor.
I'm showing here on the left side, a piece from the surgical model 
where we've conducted a midline laparotomy, exposed the uterus, 
and are using an ultrasound probe to guide injections of stems cells. 
On the right you see the ultrasound image of the fetus.
And indeed we did find that human T cells could develop in this animal model, 
and those studies are ongoing primarily at the Mayo Clinic.

04:30
The more interesting part is that hematopoietic stem cells transplanted 
into these fetal animals not only became T cells, 
they also engrafted into nonhematopoietic tissues. 
This observation has led us to utilize this model now 
for understanding how stem cells migrate, home, 
differentiate, and ultimately function in tissues. 
We've seen this in heart, lung, liver, and also in kidney.
As just one example of how understanding how stem cells develop 
might be used to improve or actually advance regenerative medicine efforts, 
we found that some of the human cells that had engrafted in these animals, 
the human cells, were actually fusion products, that is, 
they had fused with pig cells within the animal.
What I'm showing here is, on the top panel, is a cross-section from the kidney. 
The blue cells are actually human cells that in this case make up an entire tubule of the kidney.
In the bottom image, I'm showing a colabel of a pig-specific sugar, 
which is brown, and blue, again, is a human cell, 
as evidence of a fused cell within the porcine kidney.

05:48
Because of this observation and because of the fact 
that a large percentage of the human cells engrafted are in fact fused, 
we're working on studies now to ask whether 
and to which extent tissue generation could be enhanced by modulating fusion 
between stem cells and a mature, or fully differentiated, partner.
These studies have led to the development of a working hypothesis 
that we have in the lab that cell fusion directs stem cell differentiation 
and orientation in tissues, and so instead of the traditional model, 
or, actually perhaps, in addition to, where stems cells either undergo proliferation 
or differentiation, when they differentiate, interact with tissues, 
and ultimately align to form tissues, in addition, perhaps, 
stem cells confuse with fully differentiated cells, 
obtain an intermediate phenotype, whereby they are able to proliferate 
and obtain some of the functional properties of the cells within a tissue, 
and ultimately go on to form the next tissue layer or to repair an injured tissue.

06:59
I think these studies are crucial for the development of cell-based therapies 
and tissue-based therapies, but what about organ regeneration. 
Now, some might contend that stem cells could be used to drive 
developments of organs ex vivo. We are less optimistic about that.
It's been shown that stem cells can be driven to form histotypic patterns in culture. 
They can certainly be driven to function like cells in organs, 
but to actually develop anatomically complex organs in vitro, we're not so hopeful.
Instead, we would like to use a derivative of the model I suggested earlier, 
whereby human organs could be generated in a surrogate host.
And that's our next line of study 
and one where we've begun to develop two novel means to do so.
Here, I'm just showing some aortic endothelial cells that have been incorporated 
into pigs to show you just how extensive human engraftment can be 
and the potential for generating organs in a surrogate host.

08:05
With that, I'd like to thank you for your attention and to invite you, 
if you have any comments or ideas for discussion.
I've just given you a brief brushstroke of the events taking place in our lab, 
and I would welcome any interaction with you at your convenience. Thank you.