20 - Stem Cells

blood cells are the most common cell type

mature RBC lack most organelles

cell abundance ______ correlates with abundance in our bodies

negatively

human have more bacterial cells than human cells

bacterial cells dominated by colon bacteria

humancells dominated by RBC

what do the connective tissues contain

the ECM, fibers (collagen and elastic), and cells

what is tissue

a distinct combination of cells, their extracellular matrix, and their products

what this stem cell lecture is covering

how we renew dying cells

bone marrow

intestines

stem cells are basis for our different cell types

undifferentiated cells - no set “function”

change their relationship with our bodies depending on where we are in development

thee major stem cell properties

1. degree of potency

2. assymetrical cell division

3. expression of specific transcription factors and transcriptional regulators

different levels of potency

totipotent

pluripotent

multipotent

unipotent

totipotent

can produce all cell types (very early embryo stage)

pluripotent

can produce nearly all cell types (blastocyte stage, embryonic stem cells)

multipotent

can produce only within a single family of types (adult stem cells)

unipotent

one cell type

embryonic stem (ES) cell

ES cells are pluripotent that can be differentiated into (almost) any type of cell

hematopoietic stem cells are multipotent

they can differentiate various type of hematopoietic cells

asymmetrical cell division can use differences in protein abundance to maintain stem cells

cellular components will be separated differently

asymmetrical protein example

delta (ligand)/notch(receptor signaling for stem cell maintenance

once a cell differentiates, can it go back

yes, cells can go back under certain cellular conditions

what is a difference between cells

they have different transcriptional programs they undergo

during development, cells change their function and shape, which are controlled by genes

as they go more towards unipotent, the expression of pluripotency genes goes down

as they go towards totipotency, the expression of lineage specific genes goes up

how does a cell remember what is it (and not revert back to a stem cell)

1. committing to the differentiation by activating positive feedback loops

2. repressing stem cell positive gene transcription

what does committing to differentiation mean

inheritable positive feed back regulation on gene expression

patterns with totipotency chart

as you go towards unipotency, more DNA methylation

towards totipotency, more open chromatin, more lineage potential

heterochromatin formation shuts down gene expression

Histone H3 Tail Modifications:

Different modifications (Ac for acetylation, M for methylation, P for phosphorylation) at specific amino acid positions influence whether a gene is active or silenced.

H3K9 Methylation and Gene Silencing:

signal for heterochromatin formation and subsequent gene silencing.

expressino of specific transcription regulators during development can determine cell fate

regulatory proteins can change epigenetic infomration (histone modification or DNA methylation) — these will be inherited in future cell generationhow 

how can we determine what regulator proteins can make cell fate changed

cmopare genes expressed in different cell types and can predict candidate gene(s) that are responsible for differentiation (ex: skin, liver, neuron)

genes controlled by three Tfs (Klf4, Oct4, and Sox2) will have a function to reversing cell fate from differentiated to undifferentiated

these factors help reset the epigenetic information including facultative heterochromatin structure, DNA methylation

repressing Kl4, Oct 4, and Sox 2 via heterochromatin does what

and can repress “Stem-ness” and allow differentiation

evidence for cell fate determination by transcriptional regulators

reversing cell differentiation by TR, iPS cell

introduced to fibroblast nucleus, cells divide in culture, induced to differentiate in culture

iPS (induced pluripotent stem) cells

iPS could be used in similar way to ES cells

culture of fibroblasts from adult skin biopsy—> intro of DNA encoding three key TR —> iPS cell —> fat cell, neuron, macrophage, heart muscle cell, etc

iPS cells can provide tool for investigating disease releated gene function in broader aspects

iPS derived from patients

places that need constant repair or regeneration

muscles, skin, brain

places that rapidly turnover cells

skin, gut, testes, bone marrow (blood)

skin

epithelial cells in skin consistently regenerating - cells attached to basal lamia can proliferate

intestine/colon:

regeneration and differentiation of epithelial cells

bones

hematopoietic stem cell can differentiate various type of hematopoietic cells

WBCs

T lymphocyte

B lymphocyte

esoinophil

basophil

neutrophil

brain

many neurons stay in G0 permanently for function

dfferentiated neutrons (G0)

stem cels differentiate into neurons and also have to self proliferate

then stem cells!

why are neurons smth critical

1. dividing neurons could disrupt neural networks

2. loss of learning and memory

3. what if they don’t pass a checkpoint and enter apoptosis YIKES

do stem cells enter G0

yes! quiescent stem cells

muscle

upon injury, quiescent muscle stem cells activate to become myoblasts and generate new muscle tissue

quiescence → activation → proliferation → differentiation → fusion → maturation

muscle is crucial for regeneration

hydra and planaria

flatworm planaria is capable of massive regeneration

why isn’t every cell a stem cell

stem cells lack specialized properties of other cells (newborns)

if every cell could constantly renew and regenerate, cancer might be more prevalent

unregulated proliferation of cells is the origin of cancer

terminally differentiated cells should not proliferate permanently

paths that all lead to cancer

alterations in cell proliferation, alterations in DNA damage response, alteration in cell growth, alteration in cell survival

problems in gut stem cells can lead to cancer

initial stage of colon cancer

hyper proliferation of colorectal epithelial cells forming polyp

organization of intestine

regeneration and differentiation of epithelial cells

Wnt signal dictate cell fate in intestinal epithelial cells

Wnt is major signal for cell proliferation in intestine

when Wnt is available

cells respond to the signal and initiate cell division

Wnt is secreted from stromal cells near the bottom of crypt

cells located away from crypt no longer receive Wnt signal then stop dividing

mutation in Apc

unregulated Wnt signaling promotes proliferation of cells that shuold not divide, origin of polyp