Erythropoiesis: Complete Physiology Guide

What is Erythropoiesis?

1. ORIGIN - Where Does It Begin?

Sites of Hematopoiesis (changes with age)

In severe anemia or disease, the liver and spleen can restart production - called extramedullary hematopoiesis.

The Starting Cell: Pluripotent Hematopoietic Stem Cell (HSC)

Pluripotent HSC (LT-HSC)
        |
        v
Short-term HSC (ST-HSC)
        |
        v
Common Myeloid Progenitor (CMP)
        |
        v
Megakaryocyte/Erythrocyte Progenitor (MEP)
        |
        v
Erythroid-committed progenitors (BFU-E → CFU-E)

• LT-HSC = Long-term hematopoietic stem cell: self-renewing, multipotent
• CMP = Common myeloid progenitor: gives rise to red cells, platelets, and white cells (myeloid lineage)
• MEP = Bipotent progenitor for megakaryocytes/erythrocytes
• BFU-E (Burst-Forming Unit - Erythroid): earliest erythroid-committed cell; only 10-20% are actively cycling at any time
• CFU-E (Colony-Forming Unit - Erythroid): more mature; expresses the highest concentration of EPO receptors - this is where erythropoietin exerts its greatest effect

Key point: Without EPO, CFU-E cells rapidly undergo apoptosis (programmed cell death). EPO is literally a survival signal.

2. FORMATION - Stages of RBC Development

The Developmental Sequence (in bone marrow):

Proerythroblast
      ↓
Early Basophilic Erythroblast
      ↓
Late Basophilic Erythroblast
      ↓
Polychromatophilic Erythroblast
      ↓
Orthochromatophilic Erythroblast (Normoblast)
      ↓
NUCLEUS EJECTED ← [Macrophages phagocytose the nucleus]
      ↓
Reticulocyte (stays 1-2 days in marrow, then 1-2 days in blood)
      ↓
Mature Erythrocyte (circulates for ~120 days)

Each Stage Explained Simply:

Where do nuclei go? Macrophages (in the bone marrow "erythroblastic island") phagocytose the extruded nucleus. The globin is broken down, iron is recycled, and heme becomes bilirubin.

Microscopic Appearance of Erythroblast Stages

3. REGULATION - How Is Erythropoiesis Controlled?

The Central Feedback Loop

Step-by-Step Regulation Flowchart

DECREASED TISSUE OXYGENATION
(caused by: anemia, hemorrhage, high altitude, cardiac failure, lung disease)
          |
          ↓
KIDNEY senses hypoxia
(90% of EPO from peritubular fibroblast-like cells, cortex/outer medulla)
(10% from liver - insufficient alone)
          |
          ↓
HIF-2α (Hypoxia Inducible Factor-2α) accumulates
(normally degraded by VHL protein in presence of oxygen)
          |
          ↓
HIF-2α + HIF-β + HNF-4 + p300 bind to EPO gene enhancer
          |
          ↓
↑ ERYTHROPOIETIN (EPO) secretion
(Normal: 10-30 IU/L → can rise to 10,000 IU/L in severe anemia)
          |
          ↓
EPO binds to EPO-Receptors on CFU-E and early erythroblasts
          |
       ┌──┴──────────────────────────────────────────┐
       ↓                                              ↓
Rescues CFU-E from apoptosis              Accelerates maturation of
(↑ survival of progenitors)               existing erythroblasts
       └──────────────────┬──────────────────────────┘
                          ↓
              MORE PROERYTHROBLASTS formed
              More rapid transit through erythroblast stages
                          |
                          ↓ (5-7 days)
              ↑ RETICULOCYTES in blood
              ↑ MATURE RBCs
                          |
                          ↓
              IMPROVED TISSUE OXYGENATION
                          |
                          ↓
              ↓ EPO secretion (negative feedback complete)

The HIF Mechanism Explained Simply

• Oxygen present → HIF-2α is immediately tagged by the VHL protein and destroyed by the proteasome (like a fuse that burns out fast). No EPO made.
• Oxygen low (hypoxia) → VHL can't work properly → HIF-2α accumulates → enters the nucleus → turns on EPO gene → EPO is made and secreted.

4. ESSENTIAL NUTRIENTS for Erythropoiesis

5. FATE OF OLD RED BLOOD CELLS (RBC Destruction)

Senescent RBC (120 days old)
        |
        ↓
Phagocytosed by macrophages in:
  - Spleen (main site)
  - Bone marrow
  - Liver (Kupffer cells)
        |
   ┌────┴────┐
   ↓         ↓
Globin      Heme
   ↓         ↓
Amino     Fe²⁺ + Protoporphyrin ring
acids         |            |
  ↓           ↓            ↓
Reused    Recycled    Converted to
         for new       Biliverdin
           Hgb            ↓
                       Bilirubin
                          ↓
                    Bound to albumin → Liver → Conjugated
                    bilirubin → bile → excreted in feces (stercobilin)
                    and urine (urobilin)

6. KEY NUMBERS to Remember

7. SUMMARY FLOWCHART - Complete Overview

BONE MARROW
    |
Pluripotent HSC
    |
    ↓ (CMP → MEP)
BFU-E (EPO-independent)
    |
    ↓ (GATA-1 ↑)
CFU-E ←←←← EPO (most important here!)
    |          ↑
    ↓      KIDNEY
Proerythroblast    ↑ when hypoxia → HIF-2α → EPO gene → EPO
    |
    ↓
Basophilic Erythroblast (Hb synthesis starts; mitosis active)
    |
    ↓
Polychromatophilic Erythroblast (Hb increasing; last mitosis)
    |
    ↓
Orthochromatophilic Erythroblast / Normoblast
    |
    ↓ NUCLEUS EJECTED ← phagocytosed by macrophages
    |
Reticulocyte (released into blood; ~1% of RBCs)
    |
    ↓ (1-2 days)
Mature Erythrocyte
    |
Circulates 120 days → Destroyed in spleen/liver/marrow
    → Iron recycled, bilirubin excreted

8. CLINICAL RELEVANCE

• Guyton & Hall Textbook of Medical Physiology (Chapter 33)
• Brenner & Rector's The Kidney (Chapter 55 - Normal Erythropoiesis)
• Junqueira's Basic Histology, 17e
• Medical Physiology (Boron & Boulpaep)
• Histology: A Text and Atlas (Ross)