Sart Exam 2: Stem Cells

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Title: The Son of Man
Artist: Renee Magritte

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Stem Cells

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-cells w/ability to divide for indefinite periods in culture & to give rise to specialized cells

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Characteristics of Stem Cells

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-"Blank cells" - unspecialized
-capable of dividing & renewing themselves for long periods of times (PROLIFERATION & RENEWAL)
-have potential to give rise to specialized cells (DIFFERENTIATION)

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Stem Cells in Living Organisms

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-in 3-5 day old embryo (BLASTOCYST) inner cells give rise to entire body of organism, including all of the many specialized cell types & organs - heart, lung, skin, sperm, eggs, ect.
-in some adult tissues (bone marrow, muscle, brain) discrete populations of adult stem cells generate replacements for cells that are lost through normal wear & tear, injury, or dz.

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Self-Renewal

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cell that has the ability to continuously divide

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Repair

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ability to return function to damaged cells in the living organism

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Totipotent

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-each cell can develop into a new individual
-cells from early (1-3) day embryo

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Pluripotent

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-ability to develop into several different kinds of cells/tissues
-cells can form any (over 200) cell types
-some cells of blastocyst (5-14 days)

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Multipotent

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-cells differentiated, but can form a # of tissues
-fetal tissue, cord blood, & adult stem cells

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Kinds of Stem Cells

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1. Embryonic Stem Cells
2. Embryonic Germ Cells
3. Adult Stem Cells

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Embryonic Stem Cells

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-primitive (undifferentiated) cells derived from a 5-day pre-implantation embryo
-capable of dividing w/out differentiating for a prolonged period in culture
-ability to form virtually any type of cell found in the human body

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Embryonic Germ Cells

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-subset of embryonic stem cells
-derived from part of human embryo or fetus that will ultimately produce eggs or sperms (gametes)

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Adult Stem Cells

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-undifferentiated cells found among specialized or differentiated cells in tissue or organ after birth
-have more restricted ability to produce different cell types and to self renew

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Stem Cells in Research: Self-Renewal

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-scientists trying to understand 2 fundamental properties of stem cells that relate to their long-term self-renewal
1. why embryonic stem cells proliferate for years
in lab w/out differentiating, but most adult stem
cells cannot
2. what factors in living organisms regulate stem
cell proliferation & self-renewal

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Stem Cells in Research: Differentiation

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-process when unspecialized stem cells give rise to specialized cells
-while differentiating, cells usually goes through several stages, becoming more specialized at each step
-internal signals = genes
-external signals = chemicals secreted by other cells, physical contact w/neighboring cells, & certain molecules in microenvironment

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Stem Cells in Research: Adult Stem Cells

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-adult SC typically generate cells types of tissue in which they reside
-ex: blood-forming adult SC in bone marrow = hematopoietic SC:
-normally gives rise to many types of bl. cells
-cannot give rise to cells of very different tissue,
such as nerve cells in the brain

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Stem Cells in Research: Embryonic Stem Cells

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-derived from embryos
-most embryonic SC derived from embryos that develop from eggs that have been fertilized in vitro (ex vivo - in a dish) & then donated for research purposes w/informed consent of donors
-not derived from eggs fertilized in woman's body

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Stem Cell Culture

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1. growing cells in laboratory
2. human embryonic SC (hESCs) generated by transferring cells from pre-implantation stage embryo into a plastic lab culture dish containing nutrient broth (culture medium)
3. culturing ESC does not always work
4. if plated cells survive, divide, & multiply enough to crowd dish, they're removed gently & plated into several fresh culture dishes

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hESCs transferred to culture dish

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-cells divide & spread over surface of dish
-feeder layer
-devised ways to grow ESC w/out feeder cells
-significant scientific advance b/c risk that viruses/
other macromolecules in mouse cells may be
transmitted to human cells

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Feeder Layer

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-inner surface of culture dish coated w/mouse embryonic skin cells that have been treated so they will not divide
-provide cells a sticky surface to attach to
-release nutrients

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Removing Cells into Fresh Culture Dishes

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-process of re-plating or sub-culturing cells is repeated many times & many months
-each cycle of sub-culturing cells referred to as a passage
-once cell line is established, original cells yield millions of ESC
-ESCs proliferated in cell culture for 6+ months w/out differentiating = pluripotent appear genetically normal = embryonic stem cell line

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How are Embryonic Stem Cells stimulated to differentiate?

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-as long as ESC in culture grown under appropriate conditions, they can remain undifferentiated (unspecialized)
-if cells are allowed to clump together to for EMBRYOID BODIES, they begin to differentiate
-process is uncontrolled & an inefficient strategy to produce cultures of specific cell types

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Controlling Differentiation of ESCs

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-change chemical composition of culture medium
-alter surface of culture dish
-modify cells by inserting specific genes

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Adult Stem Cells in Research

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adult stem cell = somatic stem cells
-undifferentiated cell, found among differentiated cells in a tissue or organ that can renew itself & can differentiate to yield some or all of the major specialized cell types of the tissue or organ
-primary roles are to maintain & repair tissue in which they are found
-Transdifferentiation
-Reprogramming
-Induced Pluripotent Stem Cells

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Hematopoietic Stem Cells

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=forms all the types of blood cells in the body
-bone marrow stromal stem cells - generate bone, cartilage, fat, cells that support formation of blood, blood vessels, skeletal muscle, skin, teeth, heart, gut, liver, ovarian epithelium, & testis
-thought to reside in specific area of each tissue ("stem cell niche")
-stem cells may remain quiescent (non-dividing) for long periods of time until activated by normal need for more cells to maintain tissues, or by dz or tissue injury

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Neural Stem Cells

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-NSC in brain give rise to three major cells types: Nerve Cells (neurons), and two categories of non-neuronal cells - Astrocytes & Oligodendrocytes

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Epithelial Stem Cells

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-epithelial stem cells in lining of digestive tract occur in deep crypts & give rise to several cell types: Absorptive cells, goblet cells, Paneth cells, & enteroendocrine cells

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Skin Stem Cells

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-occur in basal layer of epidermis & at base of hair follicles
-epidermal stem cells give rise to keratinocytes, which migrate to surface of skin & form protective layer
-follicular stem cells can give rise to both hair follicle & epidermis

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Adult Stem Cell Culture

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-typically, there's very small # of stem cells in each tissue, & once removed from body, capacity to divide is limited, making generation of large quantities of stem cells difficult

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Transdifferentiation

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-not controlled
-certain ASC types can differentiate into cell types seen in organs/tissues other than those expected from cells' predicted lineage
-brain stem cells that differentiate into bl. cells or blood-forming cells that differentiate into cardiac muscle cells, ect.
-reported phenomenon is controversal

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Reprogramming

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-certain ASC ypes can be "reprogrammed" into other cell types in vivo using well-controlled process of genetic modification
-strategy may offer way to reprogram available cells into other cell types that have been lost/damaged due to dz.

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Reprogramming Example: pancreatic beta cells

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-insulin-producing cells that are lost/damaged in diabetes could possibly be created by reprogramming other pancreatic cells
-by "re-starting" expression of three critical beta-cell genes in differentiated adult pancreatic exocrine cells, researchers were able o create beta cell-like cells that can secrete insulin

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Induced Pluripotent Stem Cells (iPSCs)

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-reprogram adult somatic cells to become like embryonic stem cells (induced pluripotent stem cells) through INTRO OF EMBRYONIC GENES
-way to "de-differentiate" cells whose developmental fates had been previously assumed to be determined
-tissues derived from iPSCs will be nearly identical match to cell donor & thus probably avoid rejection by immune system

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De-Differentiated Cells

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-specialized
-non-specific

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Stem Cells in Application: Human Development

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-primary goal - identify how undifferentiated stem cells become differentiated cells that form tissues & organs

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Stem Cells in Application: Cancer & Birth Defects

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-due to abnormal cell division & differentiation
-more complete understanding of genetic & molecular controls of these processes may yield information about how such dz's arise & suggest new strategies for therapy

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Stem Cells in Application: Testing New Drug Therapies

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-new medications could be tested for safety on differentiated cells generated from human pluripotent cell lines
-other kinds of cell lines already used this way: cancer cell lines used to screen potential anti-tumor drugs
-availability of pluripotent stem cells would allow drug testing in wider range of cell types

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Stem Cells in Application: Cell-Based Therapies

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-donated organs/tissues replace ailing/destroyed tissue; need outweighs available supply
-SCs, directed to differentiate into specific cell types, offer possibility of renewable source of replacement cells & tissues to treat dz's (Alzheimer's, spinal cord injury, stroke, burns, heart dz, osteoarthritis & rheumatoid arthritis)
-heart muscle cells
-stem cell therapy in spinal cord injuries
-stem cell therapy in treating leukemia
-stem cells & bone dz

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Cell-Based Therapies: Heart Muscle Cells

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-goal = generate healthy heart muscle cells in lab & then transplant cells into patients w/chronic heart dz
-preliminary research in mice & other animals indicates bone marrow stromal cells transplanted into damaged heart can have beneficial effects
-whether these cells can generate heart muscle cells or stimulate growth of new bl. vessels that repopulate heart tissue
-ex: injected cells may repair be secreting growth factors, rather than actively incorporating into heart

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Unknowns in Stem Cell/Cloning Research

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-uncertain that hESCs in vitro can give rise to all different cell types of adult body
-unknown if SCs cultured in vitro (apart from embryo) will function as cells do when they're part of developing embryo

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Challenges to Stem Cell/Cloning Research

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-stem cells need to be differentiated to the appropriate cell type(s) before they can be used clinically
-recently, abnormalities in chromosome number & structure were found in three human ESC lines