Stem cell science and policy

By:

Rahul G. Thakar, Ph.D.

Wednesday June 20, 2007

Overview

• What are stem cells?

• Why use stem cells?

• Current application with stem cells.

• Public policy regarding stem cells.

Cells of the human body• The human body is

composed of many different types of cells– e.g. muscle cells, skin cells,

liver cells, nerves, cardiovascular cells, etc.

– Some are irreplaceable

• Not all cells have the same potential– Some cells remain

uncommitted - stem cells– When stem cells differentiate,

they turn into the different cells of the body

http://www.inventiveparent.com/Inside

Embryonic development

http://en.wikipedia.org/wiki/Image:StemCellsDia.png

In vitro fertilization - current method of deriving an hESC line

• Eggs and sperm donated and fused to create a fertilized egg in a petri dish

• Fertilized egg matures into a blastocyst

• Embryonic stem cells extracted from blastocyst

• Cells replated on another petri dish and grown in culture

Embryonic development

What is a blastocyst?• Trophoblast - a hollow sphere

of cells that develops into the extra-embryonic membranes such as the placenta, umbilical cord, and amnion.

• Inner cell mass (ICM) - embryonic stem cells are the ICM

http://en.wikipedia.org/wiki/Image:Blastocyst.png

Special characteristics of ALL stem cells

• Self-renewal (proliferation)- the ability of a stem cell to clone itself indefinitely by cell division.

• Asymmetric cell division – more to come

• Relocation and Differentiation are abilities of stem cells to “migrate” to where they’re needed in the body and specialize into a particular type of mature cell

Differentiation

Differentiate a stem cell can specialize into a particular type of somatic cell

Self-renew a stem cell can reproduce itself by cell division

Stem cell division and differentiation

LEGEND

A - stem cellB - progenitor cellC - differentiated cell

1 - symmetric stem cell division2 - asymmetric stem cell division3 - progenitor division4 - terminal differentiation

Generates every cell in the body including the placenta and extra-embryonic tissues

Can form the entire human being

Cannot form the entire human being

Can generate every cell in the body except placenta and extra-embryonic tissues

Become specific cell types; may or may not have plasticity

Transdifferentiation?! WHAT?

Adult stem cells• Adult stem cells are cells

found in post-natal tissue that can yield only the specialized cell types of the tissue from which they originated.

– hematopoietic stem cells – mesenchymal stem cells – umbilical cord stem cells – amniotic fluid stem cells

http://www.artsalive.ca/upload/dan/Articles_anatomy_full.jpg

Current adult stem cell therapies

Hematopoietic Stem Cell

• ESCs are derived from the inner cell mass of a blastocyst

– Can self-renew indefinitely in culture

– ESCs used for research are made in a petri dish, not a woman's body

– They hold great potential for alleviating the symptoms of or even curing:

• Paralysis• Diabetes• Alzheimer’s

Embryonic stem cells

Mouse embryonic stem cells

What is stem cell research?

• Experimental model systems, understanding more about development

• Cell-based therapies

• Pharmaceutical research and testing

Experimental model system - Cardiomyocytes

Cell-based therapy-Spinal Cord Injury

Differentiate(+ growth factors)

START

*Treatment may not work for the chronically paralyzed

time

Oligodendrocytes

Clinical trials starting for treatment of spinal cord injury* in humans(after much data gathered using ratsas an animal model)

injuredmarkedlyrecovered

Drug Development-Cancer Stem Cells

Reya, T., et al. Nature, 2001

Cell surface markers are a key difference.

Stem Cell Culture

Source: NIH

Artificially directing stem cell fate

Why do you think thisis useful?

What problems do youforesee in trying to transplant this tissueinto a human?

Mouse feeder-layer

Somatic cell nuclear transfer

Directing stem cell differentiation

W.F. Liu, 2005

Tension can dictate differentiation

R. McBeath, 2004.

Substrate elasticity is a factor as well

A. Engler, 2006.

The deliciously malicious problem

www.fda.gov/fdac/features/1999/attack.html

R.G. Thakar, et. al, 2006

Coronary heart disease accounts for 36.3% deaths in the U.S. or 1 death every 36 seconds.

Traditional solutions• Statin drugs, blood

thinning, beta-blockers, ACE inhibitors, angioplasty / stents

• These solutions are worthwhile but do not address the existing damage to the myocardium

http://www.nlm.nih.gov/medlineplus/ency/imagepages/17004.htm

Tissue engineering & the myocardium

• Approaches

– Chemical regulation• Soluble chemical factors help

regulate growth, motility, and fate• Deliver to site or evoke secretion

at the site

– Physical regulation• Biomimetic materials • Delivery of topographical cues to

promote attachment, alignment, and contractilie phenotype

• Creation of an ordered, hierarchical arrangement similar to in vivo structures

C.M. Metallo, et al., Biotechnol. Prog., 23 (1), 18 -23, 2007.

Cell sources for the myocardium

• Smooth muscles cell, skeletal myoblasts, endothelial progenitors

• Adult stem cells

• Embryonic stem cells

• Cardiac progenitors

D. Srivastava & K.N. Ivey Nature 441, 1097-1099(29 June 2006)

Our tangential studies

Orientation of neonatal cardiac myocytes grown in 3D microrod-matrigel composite

Note myofibrils in finger–like projections attaching to microrod. Also note all myofibrils are highly oriented.

Russell Lab

Morphology of neonatal myocytes. A:: NRVM in 3D gel only. B: increased myocyte size with100μm microrods and gel. C: Note finger–like projections from myocytes attaching to microrods. Actin in red, α-actinin in green, SU-8 microrods in blue.

A B C

Russell Lab

Stem cell policy

NIH’s role in federal policy

• On August 9th, 2001, President George W. Bush announced that federal funds may be awarded for research using human embryonic stem cells if the following criteria are met:

– The derivation process (which begins with the destruction of the embryo) was initiated prior to 9:00 P.M. EDT on August 9, 2001.

– The stem cells must have been derived from an embryo that was created for reproductive purposes and was no longer needed.

– Informed consent must have been obtained for the donation of the embryo and that donation must not have involved financial

inducements.

Where it stands todayPresident Bush said in mid-May 2005, "I am a strong supporter of stem cell research, but I've made it very clear to Congress that the use of federal taxpayer money to promote science that destroys life in order to save life, I am against this."

This was in response to the House and Senate passing versions of the Stem Cell Resarch Enhancement Act of 2005. G.W. Bush vetoed the act on July 19, 2006.

Again in 2007, the Senate of the new, 110th Congress passed bill S.5, Stem Cell Research Enhancement Act of 2007. On June 7, 2007, the House passed this legislation.

Acknowledgements

• Laurel Barchas

• George Gagnon

Questions