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Stem Cells from the Ground Floor. Jonathan Golob Medical Scientist Training Program University of Washington Center for Cardiovascular Biology and Regenerative Medicine Department of Pathology Doctoral Candidate.

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stem cells from the ground floor
Stem Cells from the Ground Floor

Jonathan Golob

Medical Scientist Training Program University of Washington

Center for Cardiovascular Biology and Regenerative Medicine

Department of Pathology Doctoral Candidate

what happens when we get injured or something just wears out

Tissues can repair themselves, filling the void with tough but otherwise non-functional material using the body’s equivalent of duct tape: the scar.

What happens when we get injured, or something just wears out?

Immune cells come in and clear away the debris and any infection.

Regeneration is the complete restoration of the original tissue. Damaged tissue is replaced by new functional cells.

tissues regenerate new functional cells by
Tissues regenerate new functional cells by

either dividing the existing functional cells

A stem cell must make more copies of itself (self-renew) and give rise to more capable offspring (differentiate).

or by activating an adult stem cell population.

adult stem cells can give rise to all the cells in their tissue
Adult stem cells can give rise to all the cells in their tissue.

The more capable the cell becomes, the fewer types of cells it can become.

During differentiation, cells progress down increasingly restrictive lineages.

our bodies have many adult stem cell niches
Our bodies have many adult stem cell niches

Blood

Gut

Skin

Bone, Skin, Tendon, cartilage

Liver

day 5 human embryo blastocyst stage 100 cells
Day 5 Human EmbryoBlastocyst Stage, ~ 100 cells

Trophoectoderm

(placenta and amnion)

Inner cell mass

(all tissues in the body)

1/100 inch

the inner cell mass gives rise to all the cells in the body

Ectoderm

Mesoderm

Endoderm

Germ Cells

Dorsal

Notochord

Paraxial

Bone tissue

Intermediate

Tubule cell of the kidney

Lateral

Red Blood Cell

Blood vessels

Heart

Head

Facial Muscle

Digestive Tube

Pancreatic Cell

Pharynx

Thyriod Cell

Respiratory Tube

Alveolar Cell

Germ Cells

Sperm and Egg

Outer surface

Skin

CNS

Neuron

Neural Crest

Melanocyte

The inner cell mass gives rise to all the cells in the body.
slide10
During development, the daughters of the inner cell massdifferentiate into the cell types of the body.

Gut

Endoderm

Blood

Inner

Cell

Mass

Mesoderm

Heart

Ectoderm

Skin

Brain

Germ

Sperm

Or Eggs

Time of Gestation

After Birth

the embryonic stem cell is the stem cell of stem cells
The embryonic stem cell is the stem cell of stem cells

Embryonic Stem Cell

Gut

Endoderm

Scientists have figured out how to make inner cell mass cells self-renew in plastic dishes.

A few hundred cells from one embryo can be grown into at least 1.3 × 1031 cells creating a stem cell line.

Blood

Mesoderm

Heart

Ectoderm

Skin

Brain

Germ

Sperm

Or Eggs

slide14
Discarded in-vitro fertilization clinic embryos or somatic cell nuclear transfer embryos are used to create human embryonic stem cells.

Eggs collected for in-vitro fertility treatment cannot be easily frozen and stored.

Early embryos created after the combination of sperm and eggs can be frozen.

An excess of embryos are created as the process of egg collection is painful, dangerous and expensive.

For most couples, more embryos are created than are needed to have a desired number of children.

somatic cell nuclear transfer is an alternate source of embryonic stem cells

Fertilized egg “equivalent”

Patient-Specific Stem Cells

Blastocyst

Somatic cell nuclear transfer is an alternate source of embryonic stem cells

Unfertilized egg

Fusion with patient’s cell

slide16

Patient-Specific Stem Cells

Somatic Cell Nuclear Transfer derived embryonic stem cells avoid immune rejection problems and allow the study of complex genetic diseases.

the majority of embryonic stem cell research does not create new embryonic stem cell lines
The majority of embryonic stem cell research does notcreate new embryonic stem cell lines.

Active areas of research include:

Directing the differentiation into useful cell types.

Studyingcell types that are difficult to acquire from other sources.

Studying the effect of drugs on human development.

What makes embryonic stem cells different from other stem cells and functional adult cells.

Developing new treatments for common diseases using embryonic stem cell derived cells.

review of embryonic stem cell properties
Review of Embryonic Stem Cell Properties
  • Derived from 4-5 day old embryos (Prior to implantation in uterus)
  • Indefinite proliferative capacity (“immortal”) making a stem cell line
  • Can become any cell type in the body
  • The only cells that definitely can become heart muscle cells and other clinically important cell types.
  • Allows experiments that would be otherwise impossible.
a comparison between adult and embryonic stem cells
A comparison between adult and embryonic stem cells.

Adult stem cells

Embryonic stem cells

Typically reside in or near their tissue

Created from inner cell mass cells that exist only in very early embryos

Are capable of giving rise to functional cells in their tissue (but not other tissue types)

Are typically found only in tissues that undergo regular turnover.

Are capable of giving rise to all of the cell types in the body including non-regenerative

Can be divided many times (possibly indefinitely) in culture to make many cells.

Decrease in both number and activity as one ages.

the problems we face
The Problems We Face

Leading Causes of Death in the US (2001)

CDC NCHS

the heart is an example of a non regenerative organ frequently injured
The heart is an example of a non-regenerative organ frequently injured.

Approximately one billion heartcells are lost during a serious heart attack. If one survives the initial event, a progressive chronic heart failure often occurs due to the replacement of functional beating heart cells with a tough fibrous scar.

transplantation is the current standard treatment for severe heart disease
Transplantation is the current standard treatment for severe heart disease.

2,016 heart transplants were performed in 2004.

About 2,500Americans die of cardiovascular disease each day.

If all major forms of cardiovascular disease were eliminated, life expectancy would increase by about 7 years.

instead of replacing the whole organ why not just replace the lost cells
Instead ofreplacing the whole organ, why not just replace the lost cells?

For tissues incapable of regenerating, we look towards stem cellsas a sourceof functional replacement cells.

can other tissue s adult stem cells become heart cells by transdifferentation

?

Do not exist in adults.

Can other tissue’s adult stem cells become heart cells by transdifferentation?

Blood

Inner Cell Mass

Lateral

Mesoderm

Mesoderm

Heart

Despite some early non-reproducable results, adult bone marrow cells cannot become heart, liver or brain cells.

there may be adult stem cells in the heart
There may be adult stem cells in the heart.

Various labs around the world have described four non-overlapping stem cell populations in the heart.

The data is still very incomplete for each of these cell types.

It is unclear what role, if any, is played by these cells.

An eventual goal is to activate these cells after a heart attack, or somehow augment their function.

slide26
Human embryonic stem cells have reproduciblydifferentiated into heart cells that can survive grafting into a heart.
stem cells therapies promise to tip the balance of healing more towards regeneration
Stem cells therapies promise to tip the balance of healing more towards regeneration.

Tissues resort to non-functional repair mechanisms when there is a lack of functional replacement cells either due to the properties of the tissue or the endogenous regeneration pathways being overwhelmed.

Embryonic stem cells have an unmatched and undisputed ability to become any cell type found within the body.

adult stem cells from the bone marrow cannot transdifferentiate into heart cells
Adult stem cells from the bone marrow cannot transdifferentiate into heart cells

Early attempts, using a flawed experimental approach, falsely indicated that bone marrow derived stem cells could become heart cells, against their lineage commitment.