Chapter 22 Omega

Stem cell

An undifferentiated cell that can self-renew and produce differentiated progeny to maintain tissue homeostasis.

Tissue homeostasis as a river

Tissue homeostasis is like a river: stem cells (upstream) produce progeny that flow through stages of differentiation and are lost downstream, keeping tissue steady.

Defining characteristics of stem cells

Self-renewal (make more stem cells) and potency to generate differentiated cell types for that tissue.

Progenitor cell

An intermediate, committed cell produced by a stem cell that still divides a limited number of times before differentiating.

Transit-amplifying cell

A rapidly proliferating progenitor whose divisions amplify the number of differentiated cells derived from each stem-cell division.

Terminally differentiated

A cell that has completed its differentiation program and no longer divides.

Multipotent

A stem or progenitor cell that can produce several different cell types within one tissue lineage.

Unipotent

A progenitor that produces only a single differentiated cell type.

Absorptive cell (enterocyte)

Brush-border cell that absorbs nutrients and expresses digestive enzymes.

Goblet cell

Secretory cell that produces mucus to protect the gut epithelium.

Paneth cell

Crypt cell that secretes antimicrobial proteins and Wnt signals that support the stem-cell niche.

Enteroendocrine cell

Hormone-secreting cell subtype that releases peptides/serotonin to regulate gut function.

Gut lining renewal process

Stem cells in crypts divide to make transit-amplifying progenitors that migrate up villi, differentiate into the four main cell types, and are shed at villus tips (mouse turnover ~3–4 days).

Lifespan of gut differentiated cells

Most absorptive, goblet, and enteroendocrine cells live only a few days in mice

Epidermal renewal

Basal stem/progenitor cells divide, progeny move outward, terminally differentiate into squames, and are shed, maintaining the waterproof barrier.

Cell lineage tracing

A genetic marking method that labels individual cells and follows their progeny over time to locate stem cells and determine potency.

How Lgr5 was identified

Lgr5 expression was used as a stem-cell–specific marker in lineage-tracing experiments showing single Lgr5+ cells generate all intestinal epithelial cell types (multipotency).

Why quiescent stem cells are hard to trace

Quiescent stem cells divide rarely, so lineage marks appear slowly or only after activation, making them difficult to detect by standard tracing.

Hematopoiesis

The process by which hematopoietic stem cells in bone marrow produce all blood cell lineages.

Major blood cell types

Erythrocytes (carry O₂/CO₂), granulocytes (neutrophils/eosinophils/basophils), monocytes/macrophages, lymphocytes (B/T/NK), and platelets (from megakaryocytes).

Megakaryocyte function and location

Large bone-marrow cells that fragment to form platelets

Hematopoietic hierarchy

Stem cell → multipotent progenitors (myeloid vs lymphoid) → lineage-restricted progenitors → terminally differentiated blood cells.

Stem-cell identification by transplantation

Transplanted bone-marrow fractions that rescue irradiated hosts reveal which fractions contain hematopoietic stem cells

Tissue renewal without stem cells—examples

Pancreatic β-cells and liver hepatocytes can renew by division of fully differentiated cells.

Tissues that lack stem cells

The mammalian auditory epithelium and retinal photoreceptors lack stem cells and cannot regenerate those sensory receptor cells.

Can differentiated cells dedifferentiate?

Yes—after injury some differentiated cells (e.g., Schwann cells) can revert to proliferative progenitors, and some progenitors can reprogram to stem cells.

Stem-cell niche

A specialized microenvironment of supporting cells and signals (Wnt, Notch, Hedgehog, TGF) that maintains stem-cell identity and regulates self-renewal versus differentiation.

Single Lgr5 cell forming a minigut

A single Lgr5+ intestinal stem cell embedded in extracellular matrix can form a self-organized organoid (minigut) containing all intestinal cell types, showing intrinsic self-organization of living systems.

Does niche size influence stem-cell number?

Yes—physical space and signal range of the niche limit how many stem cells can be maintained (e.g., ~15 Paneth cells define crypt niche capacity).

Possible daughter-cell fates

Daughters can either both remain stem cells (symmetric renewal) or produce one stem cell and one differentiating cell (asymmetric division).

Division-plane orientation and fate

Orientation of the mitotic spindle can asymmetrically partition fate determinants or niche contact so that one daughter inherits stem-cell fate while the other is displaced to differentiate.

Stochastic

Probabilistic or random — outcomes occur by chance rather than being deterministically fixed.

Independent-choice mechanism for daughter fate

After a symmetric stem-cell division each daughter independently chooses to self-renew or differentiate, so tissue balance is set by probabilities that can be tuned by environment or injury.

Can a young niche rescue old hematopoietic stem cells?

No — experiments show a young niche cannot rejuvenate old hematopoietic stem cells, although an old niche can still support young stem cells, indicating aging is intrinsic to the HSCs.

Planarian regeneration (S. mediterranea)

Planarians regenerate whole bodies from small fragments using abundant neoblast stem cells (≈20% of cells), some totipotent

Vertebrate organ/limb regeneration differences

Some vertebrates (e.g., salamanders) regenerate limbs/organs via proliferating lineage-restricted stem/progenitor cells and a blastema that recapitulates development, but vertebrate regeneration is generally more limited than planarian totipotent regeneration.

Neural stem cells and turnover rate

Neural stem cells persist in restricted brain regions (e.g., hippocampus, olfactory bulb). In the hippocampus ~1,400 new neurons are generated daily (~1.75% turnover per year).

Can neural stem cells be cultured?

Yes — they form neurospheres or can be expanded as purified stem-cell populations in vitro, induced to differentiate into neurons or glia, and can integrate into brain tissue after transplantation.

Nuclear transplantation reprogramming

Transplanting a differentiated nucleus into egg/oocyte cytoplasm can reset gene expression to an embryonic state by large-scale chromatin remodeling, enabling development in some cases.

Changes required for successful nuclear reprogramming

Extensive chromatin reorganization (chromosome decondensation), wholesale changes in DNA/histone methylation, replacement of histone variants (e.g., H1), and reestablishment of embryonic gene-expression programs.

Totipotent vs pluripotent vs embryonic stem cells

Totipotent: can form all embryonic and extraembryonic tissues

Reprogramming differentiated cells to pluripotency

Forced expression of transcription factors can convert differentiated cells into induced pluripotent stem (iPS) cells that behave like ES cells.

Four reprogramming (OSKM) factors

Oct4, Sox2, Klf4, and Myc — coexpression (OSKM) can reprogram fibroblasts into iPS cells.

Identifying successfully reprogrammed iPS cells

Use selection/marker strategies that report activation of endogenous pluripotency genes (e.g., Oct4 promoter-driven reporters) so only fully reprogrammed cells are isolated.

Major cellular events during reprogramming

A Myc-driven proliferation and chromatin loosening, widespread binding of Oct4/Sox2/Klf4, activation of endogenous pluripotency circuits, global changes in histone marks and DNA methylation, and establishment of self-sustaining regulatory loops.

Factors that enhance reprogramming efficiency

Manipulating chromatin remodelers, histone modifiers, histone variants, and other epigenetic regulators increases efficiency by making chromatin more accessible and lowering barriers to fate change.

Teratoma

A tumor containing a disorganized mixture of multiple tissue types (e.g., hair, muscle, cartilage) that can form when pluripotent cells differentiate uncontrolledly after implantation.

Why guided differentiation is necessary

Pluripotent cells must be driven through appropriate, timed signaling steps in culture before transplantation to generate desired cell types and to prevent teratoma formation.

Advantages of iPS cells over ES cells for therapy

iPS cells can be patient-derived (autologous) and thus reduce immune-rejection risk, unlike ES cells from unrelated embryos.

How iPS cells are used for drug discovery

Patient-derived iPS cells are differentiated into disease-relevant cell types to model pathology in vitro and to screen candidate drugs for disease-correcting effects.