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CHAPTER 74 during embryogenesis lags behind development of the myeloid and ery-
throid lineages. Although myeloid, erythroid, and natural killer (NK)
LYMPHOPOIESIS cells can be produced from all extraembryonic and embryonic sites, B
and T lymphocytes are predominantly generated from so-called defini-
tive hematopoietic stem cells (HSCs) in the embryo proper. 1

Christopher S. Seet and Gay M. Crooks MURINE HEMATOPOIETIC DEVELOPMENT
Most of the studies exploring embryonic and fetal hematopoiesis have
been performed using mouse models. Although the timing of each
SUMMARY developmental stage has been carefully mapped, it has long been a
source of controversy as to whether hematopoiesis in the embryo is ini-
Lymphopoiesis refers to the process by which the cellular components of the tiated from colonizing precursors from the extraembryonic yolk sac, or
immune system (i.e., T cells, B cells, and natural killer cells, and certain den- whether the embryonic sites of hematopoiesis arise independently from
2–6
dritic cells) are produced during hematopoietic differentiation. This process the yolk sac. This debate has implications for understanding the lin-
begins with the hematopoietic stem cell and continues through progenitor eages generated at different sites of hematopoiesis and thus for tracing
stages down a series of mostly diverging lineage pathways, ultimately result- the ancestry of the lymphoid cells that are produced in the mammalian
ing in the remarkable diversity and flexibility of the immune system. Although embryo. One reason for the difficulty in assigning the exact organ in
the more terminal events in lymphocyte differentiation and function have which lineages are generated, is that each site of hematopoiesis is active
during overlapping periods (see Fig. 74–1). In addition, once circula-
been defined in detail (Chaps. 75 to 77), the earliest events during which tion has been established, it is difficult to rule out the possibility that
hematopoietic stem cells undergo lymphoid lineage commitment are less- stem cells and progenitors found in one location did not migrate from
well understood and still controversial. Although the conceptual framework another. However studies using Ncx1 mice, which lack both heart-
–/–
for the questions of lymphoid commitment has been established largely on beat and circulation, are beginning to dissect the autonomous lineage
7,8
studies in the mouse, experimental systems now exist to better understand potentials of these distinct embryonic hematopoietic tissues.
how such events are controlled in humans. This chapter summarizes what is The first wave of hematopoiesis in the mouse begins in the
known about the ontogeny of lymphoid development and the control of lym- extraembryonic tissue of the yolk sac by 7.5 days of gestation (E7.5),
9,10
phoid differentiation, and discusses some of the persisting controversies in the before circulation is established. This initial stage of so-called prim-
field. itive hematopoiesis produces mostly erythrocytes and macrophages.
Although lymphocytes are not detectable at this time, the contribu-
10
tion of first-wave progenitors to downstream fetal lymphopoiesis has
been suggested by the identification of a lymphomyeloid progenitor in
LYMPHOPOIESIS DURING PRENATAL the E9.5 yolk sac, which expresses Rag-1, one of the earliest lymphoid-
specific events, as well as of a distinct progenitor with B-1/marginal
11
DEVELOPMENT zone B cell potential. Further studies have identified both thymic-re-
12
populating and multipotent potential in the yolk sac, 13,14 indicating
Blood is formed from a succession of sites during embryonic and fetal emerging changes to our understanding of primitive hematopoiesis.
development, beginning outside the embryo in the yolk sac. Soon The murine placenta has also been identified as an autonomous source
afterward, hematopoiesis begins in the embryo proper, initially in the of multipotent hematopoietic cells as early as E8.5 ; however, the direct
8
para-aortic splanchnopleura (PAS) and aorto-gonad-mesonephros contribution of either yolk sac or placental progenitors to definitive
(AGM) regions, then the fetal liver, spleen, and finally the fetal marrow lymphoid development remains to be determined. Definitive HSCs that
(Chap. 7). With each change of anatomical site, the range of hemato- are capable of generating all lymphohematopoietic lineages first appear
poiesis becomes progressively more complex and similar to that of the in the PAS/AGM region at E8.5 to E9. High-level, multilineage recon-
3,10
adult (Fig. 74–1). stituting activity typical of definitive HSC can be found in the murine
When assigning hematopoietic function to each developmen- AGM region by E10.5. However, although AGM cells can produce all
tal stage, it is important to distinguish the lineage “potential” of stem lineages, including T and B lymphocytes in vitro, lymphocytes do not
and progenitor cells that arise from certain areas (i.e., the ability to spontaneously develop in the fetus until hematopoiesis has begun in
generate specific lineages in vitro from immature cells removed from the fetal liver. Rag-1 expression, one of the earliest lymphoid-specific
a region) from the spontaneous physiologic production of lineages in events, can be found in the E11 murine fetal liver. T-cell potential
10
each region. With this distinction in mind, the onset of lymphopoiesis has been identified in the yolk sac and PAS as early as E8.25 to E9.5 of
murine gestation ; however, T-cell differentiation in vivo begins with
13
the colonization of the thymus around E11 by stem or progenitor cells
that migrate to the thymus from the AGM, fetal liver, and, later still, the
fetal marrow. 15,16
Acronyms and Abbreviations: AGM, aorto-gonad-mesonephros; BM, bone
marrow; BCR, B-cell receptor; CLP, common lymphoid progenitor; CT, computed
tomography; DC, dendritic cell; DN, double negative; E, days of gestation; EBF, early HUMAN HEMATOPOIETIC DEVELOPMENT
B-cell factor; FACS, fluorescence-activated cell sorting; FLT3, Fms-like tyrosine kinase Hematopoietic cells have been identified in the human yolk sac as early
3; HSC, hematopoietic stem cell; Ig, immunoglobulin; IL, interleukin; JAK3, Janus as day 18 of embryonic life, at which time, like the mouse, they are almost
kinase 3; LMPP, lymphoid-primed multipotent progenitor; LSK, lin sca-1+c-kit+; exclusively comprised of erythrocytes and, to a lesser extent, monocytes
neg
NK, natural killer; PAS, para-aortic splanchnopleura; SCID, severe combined and macrophages (see Fig. 74–1). Although no lymphocytes are seen
17
immunodeficiency. in the yolk sac, yolk sac progenitors do have NK cell potential under
certain in vitro conditions. 17,18 The same yolk sac progenitors, however,

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