Hematopoiesis

tissue homeostasis

maintenance of an adequate number of cells to carry out the functions of an organism

cellular proliferation

cellular differentiation

cell death (apoptosis)

types of tissue homeostasis

hematopoiesis

process responsible for replacing circulating cells

depends on the proliferation of precursor cells in the BM

hematopoiesis

governed by cytokines (stimulatory and inhibitory)

hematopoiesis

takes place in specialized microenvironment

hematopoiesis

where cellular proliferation and programmed cell death (apoptosis) work together

differentiation

responsible for generating diverse cell populations that provide specialized functions

commitment

defined as the instance when two cells derived from the same precursor take a separate route of development

maturation

begins with commitment and ends when the cell has all its characteristics

hematopoietic stem cells

hematopoietic progenitor cells

maturing cells

hematopoietic cells can be divided into three cellular compartments defined by their relative maturity: ?

hematopoietic stem cells

multilineage differentiation potential

quiescent

self-renewal

0.5% of total precursor cells

hematopoietic progenitor cells

restricted developmental potential (multipotent - unipotent)

population amplified by proliferation

transient without true self-renewal

3% of total precursor cells

maturing cells

committed (unipotent) population

proliferative sequence complete before full maturation

morphologically recognizable

counting differentials

>95% of total hematopoietic precursor cells

hematopoietic stem cells (HSC)

all hematopoiesis derives from a pool of these undifferentiated cells that give rise to all BM cells by the process of proliferation and differentiation

stem cell compartment

smallest of the hematopoietic precursor compartments

<0.5% of the total BM nucleated cells

multipotential precursors

capable of regenerating the entire hematopoietic system

stem cells

high self-renewal capacity

stem cells

majority are not dividing; most are at G0 in the cell cycle

stem cell phenotype

defined functionally by their ability to reconstitute both lymphoid and myeloid hematopoiesis when transplated into a recipient animal

no quantitative assays, no unique surface marker for definitive identification (not morphologically recognizable)

stem cell niches

HSCs reside in _________ in the BM by adhesion molecules and membrane-bound cytokines

adhesion molecules

membrane-bound cytokines

how HSCs reside in stem cell niches in BM

interactions between HSCs and BM stromal cells

regulate and balance the self-renewal and differentiation processes

stem cell niches

provides both a physical anchor for the HSCs and factors that regulate the number and function of HSCs

osteoblastic niche

vascular niche

2 important stem cell niches

osteoblastic niche

supports and maintains HSC quiescence and self-renewal

vascular niche

provides signals for proliferation and differentiation

apoptosis

can be triggered if the appropriate cytokines or microenvironment is not available to sustain the HSCs

limited capacity to self-renew

as HSCs divide, they generate populations of differentiating cells that have a ________________

downregulation of HSC genes and upregulation or activation of lineage-specific genes

transition of an HSc to a committed progenitor cell correlates with ?

progenitor cells

“lineage-specific transcription factors”

hematopoietic progenitor cell (HPC) compartment

upon commitment to differentiation, the stem cell enters the next compartment, the ?

HPC compartment

includes all precursor cells developmentally located between HSC and the morphologically recognizable precursor cells

progenitor cell compartment

larger than the HSC compartment - 3% of the total nucleated hematopoietic cells

does not possess cell renewal abilities

HPCs

not morphologically identifiable but are functionally defined based on the mature progeny that they produce

HPCs

mitotically more active than stem cells and can expand the size of itself by proliferation in response to the increased needs of the body

maturing cells

constitute the majority of hematopoietic precursor cells

proliferation and amplification boost these cells to >95% of the total precursor cell pool

maturing cells

exhibit recognizable nuclear and cytoplasmic morphological characteristics that can be used to classify lineage

“blast”

myeloblast - lymphoblast - megakaryoblast

earliest recognizable stage of maturing cells

hematopoietic growth factors/cytokines

specific glycoproteins that govern hematopoietic precursor cell survival, self-renewal, proliferation, an differentiation

hematopoietic growth factors/cytokines

complex and highly efficient intercellular molecular communication system

hematopoietic growth factors/cytokines

allows coordinated increases in production and functional activity without expansion of irrelevant ones

colony stimulating factors (CSF)

type of cytokines

grow factor functions

promote cel survival by suppressing apoptosis

promote proliferation

control and regulate the process of differentiation

sometimes, they can enhance the functional activity of the terminally differentiated progeny of these precursor cells

monocytes

macrophages

activated T-lymphocytes

fibroblasts

endothelial. cells

osteoblasts

adipocytes

cells that produce GFs

stromal cells

most GFs are produced by ___________ in the BM microenvironment

GFs

have multiple biological activities

many have similar or identical activities

GFs

interact with membrane receptors

GFs

can affect hematopoiesis directly or indirectly

GFs

organized into a complex, interdependent network

stem cell factor (SCF) + Flt3 ligand (FL)

2 early-acting (mutlilineage) growth factors

early-acting cytokines

primarily affect the proliferation of non-committed progenitor cells

SCF/mast cell growth factor (MSGF)

suppresses apoptosis of HSCs and promotes proliferation and differentiation of stem cells, multilineage progenitor cells, and some committed progenitor cells

promotes the survival, proliferation, and differentiation of mast cell precursors

Flt3 ligand

increases recruitment of primitive HSCs/HPCs into the cell cycle and inhibits apoptosis

Flt3 mutations

found in acute AML, encouraging growth of WBCs

later-acting (lineage-restricted) growth factors

narrower spectrum of influence and function primarily to induce maturation along specific lineages, but most are not -lineage specific

demonstrate a predominant effect on the committed progenitor cell of a single lineage, inducing differentiation of the more mature cells

G-CSF (granulocytes)

M-CSF (monocytes)

EPO

TPO

types of later-acting (lineage specific) growth factors

negative regulators of hematopoiesis

second group of polypeptides that inhibit cellular proliferation

decrease the production of stimulating factors or inhibit factors that increase growth

negative regulators of hematopoiesis

secreted in response to GFs, which limit cell proliferation after growth stimuli

negative regulations of hematopoiesis

some may contribute to the quiescent state of stem cells and early progenitors

negative regulators of hematopoiesis

upregulate cell cycle inhibitors

negative regulators of hematopoiesis

whether or not precursor cells synthesize DNA and proliferate depends upon a balance between these opposing influences

cytokines

interact with membrane receptors restricted to cells of the appropriate lineage

binding of a cytokine to its specific receptor

transduces an intracellular signal through which the particular survival, proliferation, or differentiation responses are initiated —> signaling pathways are activated

signaling molecules

will translocate to the nucleus, recruit the appropriate transcription factors, and activate or silence gene transcription

cytokine receptors

grouped according to specific structural characteristics

some are homodimers —> 2 identical subunits

heterodimers or heterotrimers

homodimers

heterodimers

heterotrimers

classifications of cytokine receptors

signal transduction pathways

transfer signals from the cytokine receptor to an appropriate response

protein tyrosine kinases (PTKs)

no intrinsic kinase activity, recruit cytoplasmic proteins to their intracellular tails that generate phosphorylation activity

receptor tyrosine kinases (RTKs)

receptor serine kinases (RSK)

receptor protein tyrosine phosphatases (PTPs)

cell surface receptors become dephosphorylated or phosphorylated by ?

intrinsic kinase activity

when phosphorylation occurs on cell surface receptors by receptor tyrosine kinases (RTKs), receptor serine kinases (RSK), or receptor protein tyrosine phosphatases (PTPs)

JAK family of PTKs

most hematopoietic receptors signal through ?

hematopoietic differentiation

regulated by differential gene expression patterns

nuclear transcription factors (TF)

establish the pattern of gene expression associated with lineage differentiation

TFs

nuclear binding proteins that interact with the regulatory promotor regions of their target genes

hematopoietic TF

more than half of the ? identified are shown to be dysregulated in hematologic malignancies

transcription factors

gene expression of gene suppression

hematopoietic microenvironment (HM)

crucial for the development of hematopoietic cells and maintains the hematopoietic system through a person’s lifetime

localized microenvironment in the hematopoietic organs

hematopoietic microenvironment (HM)

has cellular elements, extracellular components (matrix proteins and cytokines)

hematopoietic microenvironment (HM)

consists of homing and adhesion interactions that are important for the colocalization of stem cells, progenitor cells, and growth regulatory proteins within the marrow cavity

cellular components of HM

stromal cells and accessory cells —> synthesize and secrete soluble growth and differentiation factors and negative regulators as well as membrane-bound cytokines

extracellular matrix in HM

provides adhesive interactions important for the colocailzation of HSCs, HPCs, and the growth-regulatory proteins

adhesion to the microenvironment

stem cell niche

lymphoid niches

erythroid niches

megakaryocyte niches

types of hematopoietic microenvironment niches

adhesion to the microenvironment

ligand-receptor interactions —> retain HSCs in the marrow space

stem cell niches

stromal cells produce cell surface-associated factors that restrain HSC differentiation

lymphoid niches

less mature developing B cells are located closer to the endosteal surface with the more differentiated B cells nearer the sinusoidal endothelial cells

erythroid niche

erythroblastic islands

megakaryocyte niches

near the marrow sinusoidal endothelial cells, positioned to release platelets into the intravascular sinusoidal spaces