Normal Hematopoiesis

Slide 1 · Normal Hematopoiesis

Hematopoietic stem cells • lineage commitment • marrow regulation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Trace the developmental migration of blood-forming sites.

Explain HSC pluripotency, self-renewal and lineage restriction.

Connect growth factors to progenitor responsiveness and output.

Interpret marrow architecture, cellularity, aspirates and biopsies.

Slide 3 · Hematopoiesis changes location during development

The earliest blood-forming tissues are not the future adult sites.

Stem-cell populations shift from embryonic structures to fetal liver and then marrow.

The anatomical sequence explains changing sites of blood formation.

Yolk sac

AGM region

Fetal liver

Bone marrow

Slide 4 · Yolk-sac hematopoiesis begins in week three

The first blood-cell progenitors emerge in the yolk sac.

Their contribution to circulating blood is chiefly transient embryonic erythropoiesis.

This phase precedes the appearance of definitive HSCs.

Yolk-sac progenitors

Embryonic red cells

Transient blood formation

Slide 5 · Yolk-sac progeny also supply lasting macrophages

Yolk-sac-derived populations contribute to long-lived tissue macrophages.

Microglia and hepatic Kupffer cells are examples cited.

Persistent macrophage populations are distinct from transient embryonic red-cell output.

Yolk-sac progenitors

Microglia

Kupffer cells

Slide 6 · Definitive HSCs arise in the AGM region

Definitive hematopoietic stem cells appear several weeks after yolk-sac progenitors.

Their source is mesoderm in the intraembryonic aorta–gonad–mesonephros region.

These HSCs are capable of sustaining later hematopoiesis.

AGM mesoderm

Definitive HSCs

Subsequent fetal sites

Slide 7 · The fetal liver becomes the main blood-forming organ

During the third month, HSCs migrate to the developing liver.

The liver becomes the principal hematopoietic site until shortly before birth.

This dominance is temporary, unlike adult marrow hematopoiesis.

Early embryo

Third month: Liver

Fourth month: Marrow

Near birth

Slide 8 · The fetal placenta harbors hematopoietic stem cells

HSCs also reside in the fetal placenta.

The physiological contribution of this pool remains uncertain.

Cord blood collected at birth is an established transplant source of HSCs.

Placental HSC pool

Physiologic contribution: Uncertain

Clinical relevance

Cord-blood transplant source

Slide 9 · Bone-marrow colonization begins prenatally

By the fourth month of development, HSCs also settle in marrow.

The shift to marrow overlaps the period of liver hematopoiesis.

At birth, marrow throughout the skeleton is hematopoietically active.

Fetal liver

Marrow colonization

Widespread marrow at birth

Slide 10 · Hepatic hematopoiesis recedes after birth

The liver contribution falls to scattered residual foci around birth.

These residual foci become inactive soon after birth.

The marrow becomes the dominant normal site of blood-cell production.

Before birth

Liver is a major site

After birth

Residual hepatic foci become inactive

Slide 11 · Adult hematopoiesis becomes axially restricted

After puberty, active hematopoiesis largely ceases in distal bones.

In normal adults, production is predominantly within the axial skeleton.

About half of adult marrow space is hematopoietically active.

At birth

Active marrow throughout skeleton

After puberty

Activity predominantly axial

Slide 12 · One HSC population supports all blood lineages

Erythrocytes, granulocytes, monocytes, platelets and lymphocytes share an HSC origin.

HSCs occupy the apex of a progenitor hierarchy.

Diversification follows progressive restriction of cell fate.

HSC

Myeloid output

Lymphoid output

Slide 13 · Pluripotency is the breadth of HSC fate

One HSC can generate the major mature blood-cell lineages.

Lineage breadth is lost progressively in downstream progenitors.

The result is a large repertoire of mature cells from a small upstream compartment.

Pluripotent HSC

Red cells

Granulocytes

Monocytes

Platelets

Lymphocytes

Slide 14 · Self-renewal maintains the stem-cell compartment

HSC maintenance requires a daughter cell to retain stem-cell identity.

Self-renewal prevents exhaustion of the HSC pool.

Differentiation can proceed in parallel with retention of stem cells.

HSC division

HSC retained

Differentiating progeny

Slide 15 · Adult HSCs are few relative to their total output

Roughly 50,000–200,000 HSCs in normal adult marrow.

These cells underpin the lifelong renewal of circulating blood cells.

Their numerical scarcity makes preservation of self-renewal essential.

50,000–200,000

Estimated adult marrow HSCs

Slide 16 · Multipotent progenitors amplify production

Some HSC divisions give rise to multipotent progenitors (MPPs).

MPPs proliferate more readily but have less self-renewal capacity than HSCs.

They connect durable HSC maintenance to high-output differentiation.

HSC

Multipotent progenitor

Restricted progenitors

Mature blood cells

Slide 17 · Lineage commitment is a progressive restriction

Early progenitors still have more than one developmental option.

Later progenitors have increasingly constrained lineage potential.

Morphologically identifiable precursors emerge after these commitment steps.

Broad potential

Restricted potential

Recognizable precursor

Mature cell

Slide 18 · Myeloid progenitors generate several mature classes

The myeloid pathway gives rise to granulocytes and monocytes.

Erythroid and megakaryocytic differentiation also proceed within the myeloid arm.

Distinct downstream precursors account for the divergent mature phenotypes.

Myeloid potential

Granulocytes

Monocytes

Red cells

Platelets

Slide 19 · Lymphoid progenitors produce B, T and NK cells

Early lymphoid progenitors enter distinct differentiation pathways.

The Robbins lineage figure depicts B cells, T cells and natural killer cells.

Committed B-, T- and NK-cell precursors precede terminally differentiated cells.

Lymphoid potential

B cells

T cells

NK cells

Slide 20 · Colony-forming units identify restricted progenitors

Some committed progenitors are defined by colonies formed in culture.

The term CFU refers to these experimentally recognizable colony-forming units.

Colony type reflects a progenitor’s increasingly constrained differentiation capacity.

Committed progenitor

Cell division in culture

Lineage-specific colony

Slide 21 · Maturing blood cells pass through recognizable stages

Committed progenitors generate precursors with identifiable morphology.

Examples include myeloblasts, erythroblasts and megakaryoblasts.

These recognizable cells are closer to mature output than the upstream HSC pool.

Multipotent progenitor

Committed progenitor

Morphologic precursor

Mature cell

Slide 22 · Neutrophil production proceeds through the granulocytic arm

The source hierarchy places neutrophils downstream of myeloid progenitors.

Myeloblasts are a morphologically recognized granulocytic precursor.

Subsequent maturation generates circulating granulocytic cells.

Myeloid progenitor

Granulocytic precursor

Neutrophil

Slide 23 · Eosinophil and basophil paths are distinct

The lineage schematic identifies eosinophil-committed and basophil-committed precursors.

Eosinophiloblast and basophiloblast forms precede their mature granulocytes.

A shared early myeloid origin does not imply identical terminal differentiation.

Eosinophil branch

Eosinophiloblast → eosinophil

Basophil branch

Basophiloblast → basophil

Slide 24 · Monocyte production passes through monoblasts

A committed monocytic progenitor lies downstream of the myeloid compartment.

Monoblasts are the recognizable precursor depicted in the source figure.

Their maturation yields circulating monocytes.

Myeloid potential

Monocytic progenitor

Monoblast

Monocyte

Slide 25 · Erythroid differentiation culminates in nuclear extrusion

Erythroid progenitors pass through erythroblast stages.

Before release, developing red cells extrude their nuclei.

Marrow macrophages remove the resulting nuclear remnants.

Erythroid progenitor

Erythroblast

Nuclear extrusion

Erythrocyte

Slide 26 · Megakaryocytic differentiation yields platelets

Megakaryocyte progenitors generate megakaryoblasts and mature megakaryocytes.

Mature megakaryocytes extend cytoplasmic processes toward sinusoidal blood.

Budding processes release platelets into the circulation.

Megakaryocytic progenitor

Megakaryocyte

Platelet release

Slide 27 · Committed progenitors trade renewal for production

Downstream commitment progressively curtails self-renewal.

At the same time, progenitors undergo extensive factor-responsive proliferation.

Their amplified progeny differentiate and eventually undergo terminal cell death.

HSC compartment

Durable self-renewal

Committed compartment

Rapid expansion → finite life

Slide 28 · Stem cells and mature elements solve different problems

HSCs preserve a renewable source of every blood lineage.

Progenitors supply a rapidly expanding production compartment.

Terminally differentiated blood cells perform specialized functions for finite lifespans.

Long-term HSC reserve

High-output progenitor pool

Specialized mature effectors

Slide 29 · The HSC hierarchy is a biological model, not a smear

Most experimental evidence for the classic hierarchy comes from murine studies.

Human hematopoiesis is believed to follow comparable principles.

Do not apply murine-specific marker combinations figure as human diagnostic criteria.

Experimental framework

Much evidence derives from mice

Human application

Similar overall organization is inferred

Slide 30 · HSC self-renewal occurs within a specialized niche

The marrow contains localized microenvironments supporting HSCs.

The niche enables stem-cell maintenance while allowing production of progeny.

This arrangement protects the long-lived source population.

HSC

Stromal support

Soluble factors

Slide 31 · Stromal cells and secreted factors jointly support HSCs

Niche stromal cells nurture and protect the HSC pool.

Locally secreted factors form part of the supportive environment.

Niche signaling is distinct from the later lineage-specific growth-factor response.

Stem-cell niche

Stromal support

Secreted factors

Slide 32 · A division must preserve at least one stem-cell descendant

HSC output cannot be sustained if every division consumes both stem-cell daughters.

Self-renewing progeny replenish the durable reservoir.

Another descendant may enter the progenitor differentiation pathway.

HSC division

Renewed HSC

Committed progeny

Slide 33 · HSCs are mobile rather than fixed in marrow

Developmental site-to-site migration demonstrates HSC mobility.

Even after marrow residence is established, HSCs can enter peripheral blood.

Mobilization becomes more conspicuous during hematopoietic stress.

Marrow niche

Mobilization

Peripheral blood

Slide 34 · Hematopoietic stress promotes HSC mobilization

Severe anemia and acute inflammation are examples given in the source.

These stresses are associated with increased circulating HSCs.

The response links systemic need to movement of the stem-cell compartment.

Severe anemia

Demand for blood-cell replacement

Acute inflammation

Heightened hematopoietic stress

Slide 35 · G-CSF can mobilize transplantable HSCs

G-CSF is one of the factors capable of dislodging HSCs from their niches.

Donors treated with G-CSF provide circulating HSCs for collection.

Peripheral blood has become a major source for HSC transplantation.

Donor marrow HSCs

G-CSF mobilization

Peripheral collection

Transplant HSC source

Slide 36 · Finite cell lifespans require continuous production

Circulating blood elements are terminally differentiated cells.

Because they do not persist indefinitely, the marrow must continually replace them.

The production system combines a renewing stem-cell reserve with expanding progenitors.

Mature cells

Finite lifespan

Replenishment

Marrow output

Slide 37 · Short-term marrow responses act on committed progenitors

Growth factors regulate the quantity of lineage output.

Committed progenitors are especially responsive to these factors.

The HSC pool need not directly produce every fluctuation in circulating cell count.

Physiologic demand

Growth-factor signal

Progenitor expansion

Mature-cell output

Slide 38 · CSFs are named for their effect in culture

Colony-stimulating factors support colonies of blood cells in vitro.

The name captures the discovery method rather than a single cellular target.

Different factors act at different levels of hematopoietic commitment.

Cultured progenitor

Growth factor supplied

Colony formation

Slide 39 · KIT and FLT3 ligands act relatively early

KIT ligand and FLT3 ligand support early committed progenitors.

Their receptors occur before the most lineage-restricted maturation stages.

They differ in target distribution from downstream lineage-specific factors.

Early progenitors

KIT ligand; FLT3 ligand

Restricted progenitors

EPO; GM-CSF; G-CSF; TPO

Slide 40 · Erythropoietin supports the erythroid pathway

Erythropoietin is a lineage-directed hematopoietic growth factor.

Its effects are chiefly expressed through erythroid committed progenitors.

Expansion of this compartment contributes to increased red-cell production.

Erythropoietin

Erythroid progenitor

Erythroblast output

Red cells

Slide 41 · G-CSF drives granulocytic lineage responsiveness

G-CSF is among the factors acting mainly on restricted progenitors.

Granulocyte output can rise under cytokine and growth-factor direction.

G-CSF additionally has a distinct role in HSC mobilization.

G-CSF

Granulocytic response

HSC mobilization

Slide 42 · GM-CSF regulates committed myeloid production

Granulocyte–macrophage CSF is included among lineage-related regulators.

It acts largely through receptors on committed progenitors.

This illustrates how growth-factor specificity accompanies lineage restriction.

GM-CSF signal

Committed myeloid cells

Amplified myeloid output

Slide 43 · Thrombopoietin targets the platelet-producing lineage

Thrombopoietin is listed among the principal lineage-related growth factors.

Receptors on committed progenitors couple signaling to platelet-lineage output.

Platelets originate from mature megakaryocytes in marrow.

Thrombopoietin

Megakaryocytic progenitor

Megakaryocyte

Platelets

Slide 44 · Feedback aligns production with peripheral demand

Lineage-specific factors participate in feedback control of marrow output.

The effective response is changed proliferation of committed progenitors.

Such loops maintain appropriate numbers of red cells, white cells and platelets.

Peripheral demand

Growth factors

Progenitor expansion

Cell replacement

Slide 45 · Inflammation can increase granulocyte production

The marrow contributes a major cellular supply to innate host defense.

Infectious or inflammatory signals recruit growth factors and cytokines.

Increased granulocytic production is an adaptive marrow response.

Infection / inflammation

Cytokine signaling

Marrow granulopoiesis

Increased output

Slide 46 · Growth factors differ by their progenitor targets

Early progenitors respond to relatively broad-acting KIT and FLT3 ligands.

More restricted compartments respond to EPO, GM-CSF, G-CSF and TPO.

The stage of commitment shapes what response a factor can elicit.

Growth factor

Principal compartment

Illustrative output

KIT / FLT3

Earlier committed

Early response

EPO

Erythroid

Red cells

G-CSF / GM-CSF

Myeloid

Granulocytes / monocytes

Thrombopoietin

Megakaryocytic

Platelets

Slide 47 · Bone marrow integrates cell growth and blood release

The marrow houses proliferating progenitors and differentiating precursors.

Its sinusoidal vasculature creates a channel for mature-cell entry into blood.

Supportive interstitial cells and fat coexist with hematopoietic elements.

Hematopoietic interstitium

Sinusoid

Schematic — not histology

Slide 48 · Marrow sinusoids are thin-walled vascular channels

Sinusoids are lined by a single layer of endothelial cells.

A discontinuous basement membrane and adventitial cells lie beneath the endothelium.

These features are part of the marrow’s specialized exchange interface.

Marrow interstitium

Sinusoidal blood

Thin endothelial lining

Slide 49 · Hematopoietic clusters occupy the interstitium

Hematopoietic cells form interstitial clusters between sinusoids.

Fat cells occupy spaces within the same marrow compartment.

The balance between the two changes with marrow activity and disease.

Hematopoietic interstitium

Sinusoid

Schematic — not histology

Slide 50 · Mature cells leave marrow by crossing endothelium

Differentiated blood cells enter sinusoidal channels.

Transcellular migration through endothelial cells.

Production and controlled release are therefore distinct marrow functions.

Marrow interstitium

Sinusoidal blood

Cell passage

Slide 51 · Megakaryocytes are positioned close to sinusoids

Mature megakaryocytes lie adjacent to marrow vascular channels.

They send cytoplasmic processes into the sinusoidal circulation.

Platelets bud from these projections directly into blood.

Marrow interstitium

Sinusoidal blood

Megakaryocyte

Slide 52 · Erythroblasts assemble around supportive macrophages

Red-cell precursors often surround a central marrow macrophage.

This spatial organization is associated with terminal erythroid maturation.

Macrophages dispose of nuclear remnants after enucleation.

Macrophage

Erythroid precursors

Schematic cell grouping

Slide 53 · An erythroid nucleus is cleared before circulation

Developing erythrocytes eject their nucleus before release.

The central macrophage removes the residual nuclear material.

This local clearance supports orderly production of anucleate red cells.

Erythroblast

Nucleus extruded

Macrophage clearance

Mature erythrocyte

Slide 54 · Marrow aspirates best show precursor cytology

Aspirated marrow smears allow direct assessment of individual cell morphology.

More mature precursor classes may be identified on morphology alone.

This strength differs from the architectural assessment of a core biopsy.

Aspirate smear

Cell-level morphology

Core biopsy

Architecture and activity

Slide 55 · A blast cannot be assigned lineage on appearance alone

Immature marrow precursors of different lineages can look similar.

Lineage-specific antibodies and histochemical markers are needed for reliable typing.

The distinction between blast identification and lineage assignment is essential.

Mature precursor

Often recognizable morphologically

Immature blast

Lineage markers required

Slide 56 · Core biopsy provides a measure of marrow activity

A biopsy retains tissue architecture for judging cellularity.

Cellular elements can be evaluated relative to marrow fat.

Focal architectural disorders are more readily appreciated in a tissue core.

Aspirate

Dispersed cells

Biopsy

Tissue pattern and cellularity

Slide 57 · Normal adult marrow contains cells and fat

A normal adult fat-to-hematopoietic ratio of roughly 1:1.

A biopsy reveals whether blood-forming elements occupy expected space.

This estimate is a baseline for contrasting hypo- and hypercellular states.

Fat ≈ hematopoietic elements

Relative proportions illustrated schematically; Not measured

Slide 58 · Hypoplasia is associated with excess marrow fat

In aplastic anemia, hematopoietic elements are markedly reduced.

The proportion of fat cells rises as the marrow becomes hypoplastic.

Low blood counts may thus reflect reduced marrow production rather than peripheral loss.

Fat predominates

Relative proportions illustrated schematically; Not measured

Slide 59 · Compensatory hyperplasia reduces the fat compartment

When marrow demand increases, hematopoietic cellularity may expand.

Hemolytic anemia is one example associated with compensatory hyperplasia.

The relative area occupied by fat consequently contracts.

Hematopoietic elements predominate

Relative proportions illustrated schematically; Not measured

Slide 60 · Marrow tumors can replace normal fat and cells

Hematopoietic neoplasms may occupy large portions of marrow space.

The normal adipose compartment may diminish or disappear.

Clonal expansion can simultaneously impair normal marrow production.

Normal compartments displaced

Relative proportions illustrated schematically; Not measured

Slide 61 · Fibrotic marrow may yield an unsuccessful aspirate

Metastatic cancers and granulomatous conditions may induce local marrow fibrosis.

An aspiration attempt can fail when tissue is fibrotic.

A core biopsy is then better suited to seeing the underlying lesion.

Aspiration

May be a dry tap

Trephine biopsy

Can reveal fibrosis or infiltration

Slide 62 · Architectural distortion can cause leukoerythroblastosis

Marrow distortion may force immature precursors into circulation.

Robbins calls this abnormal circulating mixture leukoerythroblastosis.

Metastatic tumor deposits and granulomatous conditions are example causes.

Distorted marrow architecture

Premature precursor release

Leukoerythroblastosis

Slide 63 · Production failure may affect one or several lineages

Hematopoiesis may be suppressed by genetic conditions, infection or toxins.

Nutritional deficiencies and chronic inflammation can also impair output.

The resulting deficit may involve one or more circulating blood-cell types.

Impaired hematopoiesis

Red-cell deficit

White-cell deficit

Platelet deficit

Slide 64 · Neoplastic mutations can arrest differentiation

Some blood-cell tumors acquire defects that block progenitor maturation.

Immature neoplastic populations can expand without producing normal mature output.

Such clonal expansion may replace healthy marrow progenitors.

Mutation

Maturation block

Clonal cell expansion

Marrow displacement

Slide 65 · Neoplastic cells may escape growth-factor control

Mutations may also abrogate normal growth-factor dependence.

Growth becomes dissociated from the physiologic feedback that limits cell production.

This contributes to unregulated clonal expansion in marrow and beyond.

Normal hematopoiesis

Factor-tuned, demand-responsive

Neoplastic growth

Abnormally autonomous expansion

Slide 66 · Neoplasms may begin at different hierarchy levels

Some arise from HSCs and retain capacity for multilineage differentiation.

Others originate in restricted progenitors that acquire abnormal self-renewal.

The cell of origin helps explain phenotypic breadth across neoplasms.

Clonal origin

Transformed HSC

Progenitor with acquired renewal

Slide 67 · Case: Interpreting a fat-rich marrow biopsy

A patient has reduced circulating blood counts and a markedly fat-rich marrow core.

The tissue pattern indicates reduced hematopoietic activity.

Aplastic anemia is a model of this hypoplastic morphology; A final diagnosis requires context.

Observed pattern

Fat-rich, few hematopoietic cells

Mechanistic interpretation

Marrow production failure

Slide 68 · Case: Interpreting immature cells in peripheral blood

A blood smear shows abnormal release of immature myeloid and erythroid forms.

Consider disruption of normal marrow architecture.

Evaluate infiltration or fibrosis with tissue sampling in the appropriate setting.

Immature precursors in blood

Architectural disturbance

Evaluate marrow

Slide 69 · Case: Understanding a dry marrow tap

Aspiration produces little marrow despite suspicion of infiltration.

The result does not rule out a substantial marrow lesion.

Fibrosis or focal infiltration is better evaluated in a core biopsy.

Aspirate

Nondiagnostic or absent

Biopsy

Architecture may reveal lesion

Slide 70 · Hematopoiesis connects hierarchy, feedback and tissue architecture

HSCs preserve lineage potential and long-term renewable capacity.

Committed progenitors translate growth-factor signals into rapid cell output.

The marrow microenvironment organizes maturation and release into blood.

HSC + niche

Factor-responsive progenitors

Marrow maturation + release

Circulating blood

Slide 71 · Recognize three principal marrow response patterns

Hypoplasia: Loss of hematopoietic elements and relative fat expansion.

Hyperplasia: Increased hematopoietic elements and relative fat reduction.

Distortion or fibrosis: Altered release and possible dry-tap aspiration.

Hypoplasia

Relative fat excess

Hyperplasia

Relative hematopoietic excess

Distortion / fibrosis

Premature release or dry tap

Slide 72 · Explain blood-cell output by asking four questions

Is the renewable HSC compartment preserved?

Which progenitor lineage and growth-factor signals are active?

Can cells mature and traverse marrow sinusoids normally?

Does marrow architecture permit effective hematopoiesis?

HSC reserve

Lineage program

Maturation / release

Marrow architecture

Slide 73 · Primary source and interpretation boundaries

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th ed. Chapter 13, “Normal Hematopoiesis,” pp. 531–533.

The illustrations are original editable schematics—not diagnostic specimens or reproductions of textbook images.

Adult ranges from the extracted Table 13.1 are omitted because unit symbols in the Markdown conversion are corrupted; consult the printed table and local laboratory ranges.