Dr. Doris Taylor presents "Building New Hearts: Regenerative Medicine Becomes a Reality" at the Banff Transplant Pathology meeting in Vancouver October 5, 2015.

1. Building New Hearts: Regenerative Medicine
Becomes a Reality
Texas Heart Institute Regenerative Medicine Research
Doris A. Taylor, Ph.D., D.Sc. (hon), FAHA, FACC
Vancouver, British Columbia
October 5, 2015

2. Worldwide Burden of Cardiovascular Diseases

3. Repair isn’t enough; the unmet need
is organs for transplant
Coronary
Athero-
sclerosis
Acute MI
Post-AMI
Heart
Failure
End Stage
Heart
Failure
874,000 people die each year from
heart disease
• 2,600 patients wait for approximately
2,300 hearts each year

4. 4
The unmet need for organs
4
0
10000
20000
30000
40000
50000
60000
70000
1995199619971998199920002001200220032004200520062007200820092010201120122013
Transplants
Deceased Donors
Living Donors
Number on Waiting List
Source: OPTN: Organ Procurement and Transplantation Network
NumberofPeople

5. If it were
easy,
someone
else
would
have done
it…

6. 6
What does it take to build a complex
solid organ?
Billions of Cells
• Bone marrow
• Blood
• Tissue Bx
• iPS cells
• ES cells
A Scaffold
• Biologic
(ECM)
• Synthetic
• Bioprinting
Ability to put it
together
• Pump
function
• Metabolism
• Physiology

7. 7
Biologic matrices (Eschenhagen)
DEVICES
Prometheus
Frenesius
Bioprinting
QuickTime™ and a
decompressor
are needed to see this picture.
Decellularized
cadaveric organs
Scaffold Options

8. 8
Building Scaffolds
Utilizing xenogeneic or non-transplantable organs as scaffolds for
re-building tissues with stem cells
Cadaveric heart
Use detergent
to remove cells
Decellularized heart
(extracellular matrix only)

10. 10
Why decellularized ECM instead of
devices or bioprinting?
14 days
3 days
STRUCTURE
Recapitulates the organ
Cells respond to
composition
FUNCTION
Nature knows how to
do it
COMPOSITION
Simple vs. complex
Decades of experience
(infarct vs. healthy heart
scaffold)

11. 11
Human organs are not suitable for
transplant
Day 0
Day 3

12. 12
Human-sized organ scaffolds: Porcine

13. 13
Structure is retained after removal of all
cells
SABIO – Sanchez, Aviles…Taylor

14. 14
Acellular vessels retain blood
SABIO – Sanchez, Aviles…Taylor

15. 15
Complex ECM with GFs, sugars & mechanical properties
Composition is a major advantage

16. 16
Stem Cell Sources
• iPS cells
• Reprogrammed skin/blood cells
• Cord blood cells/Amniotic fluid cells
• Tissue-derived stem cells:
o Blood
o Bone marrow
o Fat
o Muscle
•
• Revitalized bone marrow or fat stem cells

17. 17
dECM + cardiac derived cells
dECM dECM + CMs

18. 18
What can we build?

19. 19
Cardiac valves: scaffold intact

20. 20
Acellular valves are competent

21. 21
Valves can be engineered

22. 22
Creating a Beating Heart in the Lab
Step 1. Cardiac Patches as a tool for repair or delivery
Step 2. Bio-Artificial Hearts for Transplant
“d-ECM patch”
applied day 3 post MI
vs. sham treatment
Decell rat heart
LV or RV

23. 23
Edge of patch suggests integration,
vascularization & cell recruitment

24. 24
Creating a Beating Heart in the Lab
+/- Cells
Step 1. Cardiac Patches as a tool for repair or delivery (porcine)
Step 2. Bio-Artificial Hearts for Transplant

25. 25
Veins and trabeculae
Vascularized heart is an unmet need
Acellular vessels are patent

26. 26
Creating a Beating Heart in the Lab
Step 1. Cardiac Patches as a tool for repair or delivery (porcine)
Step 2. Revascularized bio-artificial hearts
Coronary arteries

27. 27
Coronary arteries
Veins and trabeculae
Whole heart - labeled cells perfused
into artery and veins
Recellularization of acellular coronary
vessels via infusion of cells

28. 28
PLoS One. 2014; 9(2): e90406.
Published online Feb 27, 2014. doi: 10.1371/journal.pone.0090406
Large & small diameter vessels re-
lined throughout the heart

29. CMFDAeNOS
CMFDAvWFCMFDAPCNA
Di-ODi-IDAPI
PLoS One. 2014; 9(2): e90406. Published online Feb. 27, 2014. doi: 10.1371/journal.pone.0090406
Vascular cells proliferate & “function”

30. 30
Decellularization Recellularization
Technology to create
cardiac scaffold from any
species
Technology for stem cells
to repopulate scaffold into
beating heart
+ =
Creating a Beating Heart in the Lab
A BEATING
HEART

31. 31
Steps of creating a beating heart in
the lab
Heterotopic
Transplant
Step 2. Revascularized hearts
Step 3. Bio-Artificial Hearts for Transplant

32. 32
Creating a Beating Heart in the Lab
Heterotopic
Transplant
Step 2. Revascularized hearts
Step 3. Bio-Artificial Hearts for Transplant

33. 33
Hurdles
• Organ complexity
Atria, Ventricle, Pacemaker, Neurons, Fibroblasts, Stem cells
• Billions of cells at an affordable cost
• Once we have cells … organ potency
o Longevity – years and years
o Endogenous responsively/repair
o Physiologic response
Progenitor cells
Cardiac stem cells
Endothelial
cardiomyocytes
Smooth muscle cells
Numbers
Types

34. 34
Potential Therapies
0
Drug Testing
Therapeutics
New Cells
MarketSize
$200M
$$$B
$2B
“Organ in a dish”
Matrix + Cells
Organs for
Transplant
Matrix + Cells
Cardiac
Patch
1
2
3
Liver
Assist
Device
Liver
Heart
Kidney
Pancreas
Lung
Time

35. 35
Conclusions
The unmet
need is
organs for
transplant
dECM
provides
optimal
advantages
as a scaffold
The door is
open for
complex
human organ
engineering
Regenerative
medicine is
coming of
age
The rate-
limiting step
is CELLS

36. And then there’s this…

37. 37
We’ve got that covered too
Liver

38. 38
human hepatocytes live for a
month

39. 39
And then when you want to get rid of
that drink…
Decellularized
Porcine kidney

40. THANK YOU
I WISH I WERE THERE
First they ignore you,
then they laugh at you,
then they fight you,
then you win.
Mahatma Gandhi

41. National Institutes of Health/NHLBI
AHA DeHaan Foundation
EU SABIO Project
UT School of Public Health
Texas Heart Institute
Deep in the Heart of Texas