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

Embryonic development

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

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 cell B - progenitor cell C - differentiated cell 1 - symmetric stem cell division 2 - asymmetric stem cell division 3 - progenitor division 4 - 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

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 rats as an animal model) injured markedly recovered

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 this is useful? What problems do you foresee in trying to transplant this tissue into 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 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

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), , 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, (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 BC 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, –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 today President 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 G.W. Bush vetoed the act on July 19, Again in 2007, the Senate of the new, 110th Congress passed bill S.5, Stem Cell Research Enhancement Act of On June 7, 2007, the House passed this legislation.

Acknowledgements Laurel Barchas George Gagnon

Questions