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The transformation of adipose tissue into hemocytopoietic tissue.

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T H E TRANSFORMATION OF ADIPOSE TISSUE INTO
HEMOCYTOPOIETIC TISSUE
H. E. JORDAN
Laboratory of Histology and Embryology, University of Virginia
The usual sites of extramedullary blood formation in man
and mammals are the spleen and the lymph nodes. These
organs in man frequently become hemopoietically active in
certain cases of anemia and leukemia. The myeloid nietaplasia apparently represents a reaction compensatory to a
morbid bone marrow. Additional ectopic hemocytopoietic
areas in the adult may occur in the periportal regions of the
liver and in the kidneys, where the reticular connective tissue
constitutes the source of the differentiating hemoblasts. I n
many cases of extramedullary blood development in man, the
condition may extend also in variable degree to certain lobules
of adipose tissue, more commonly those of the prevertebral
abdominal region and those adjacent t o the kidneys.
This investigation is concerned especially with a study of
the histogenetic process by which adipose tissue in relation
to the kidneys and certain lymph nodes becomes converted
into erythrocytopoietic tissue. The matter is of especial importance because of its bearing on the problem of the manner
in which hypoplastic (fatty) marrow changes to the hyperplastic condition. The fundamental questions iiivolved in
this process concern the source of the erythrocyte precursor,
whether endothelial cell, lymphocyte or reticular cell ; and the
condition of the lining of the erythrocytopoietic capillaries
and sinusoids, whether complete or fenestrated.
MATERIALS AND METHODS
The normal material includes kidneys of the cat in which
the vascular system was injected with carmine gelatin. The
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T H E A N A T O X I C A L REOORD, VOL. 59, NO. 4
462
H. E. JORDAN
injection passed to the capillary system of the tunica adiposa
of the capsule. This adipose tissue supplies the material
for the study of the fat-cell-capillary relationship in normal
fat.
The pathological material showing extramedullary hemocytopoiesis in adipose tissue includes the kidneys and lymph
nodes from a case of adenocarcinoma of the prostate. The
tumor had metastasized widely and extensively, having invaded all abdominal organs except the spleen. The bone
marrow was largely replaced by the tumor tissue and almost
all of the lymph nodes were greatly enlarged and entirely
replaced by the tumor. However, in the case of a few of the
larger lymph nodes a small polar area remains free of the
carcinoma. Such areas have in part the appearance of hemal
node tissue, in part they resemble more closely red bone marrow. In the latter case there is considerable fat. Furthermore, the fatty tissue adjacent to many of these lymph nodes
shows a variable degree of myeloid (erythroid) metaplasia.
These fatty areas supply the material for the study of the
process of origin of the hemocytopoietic tissue. The material
was fixed with Helly’s fluid, and stained either with the Giemsa
stain o r hematoxylin and eosin.
I n addition, sections of the developing femur were studied
for information regarding: first, the earliest stages in the
formation of marrow and the relation between the ancestral
blood cells and the primitive vascular system; and secondly,
the alterations effected by the appearance of fat cells during
the conversion of a primitive hyperplastic marrow into a
secondary hypoplastic fatty marrow in the diaphysis.
The problem was pursued further with femoral marrow
of the adult cat. This material includes marrow in extreme
hypoplastic condition following suprarenalectomy, and marrow in early stages of restoration following administration of
cortical extract. For the cat material I am indebted to Prof.
S. W. Britton.
BLOOD FORMATION I N ADIPOSE TISSUE
463
T H E RELATION BETWEEN T H E FAT CELLS AND T H E CAPILLARIES
I N NORMAL ADIPOSE TISSUE
The adipose tissue under consideration is that in relation
to the renal capsule. The blood vessels were filled with carmine gelatin injected into the renal artery. Sections were
cut a t 20 1-1 and lightly stained with hematoxylin. The capillary supply is very profuse, the mesh of the intricate network
having approximately the diameter of the fat cells. Many
fat cells are almost completely encircled by a delicate capillary; the smaller branches may arise a t right angles from
parent stems and may be sharply flexed into one complete
spiral near the point of origin. The capillary beds connecting arterioles with venules are of typical form and arrangement; the system is completely closed, and includes no elements comparable to the long straight non-anastomosing
arterial (transition) capillaries and the related venous sinuses
of the bone marrow, nor the penicillus and related sinuses of
the spleen. With this morphology as a background we are
in a position to attempt the interpretation of conditions in
areas of myeloid (erythroid) metaplasia in adipose tissue.
T H E HISTOGENESIS O F BLOOD I N ADIPOSE TISSUE
The process of erythroid metaplasia is identical in the fatty
tissue of the renal hilus and that covering certain lymph nodes
in the case of the metastasizing adenocarcinoma of the prostate. Accordingly, the following description applies to either
region. The first indication of a prospective area of hemocytopoietic tissue is the accumulation of cells resembling small
lymphocytes about certain capillaries and precapillary veins.
These accumulations enlarge, many of the cells having meanwhile assumed the characteristics of large lymphocytes or
hemocytoblasts. These areas may include also a few megakaryocytes. The included capillaries and venules have become
invaded by hemocytoblasts ; these cells are in process of differentiation within the lumen of the blood vessels. Many of
the hemocytoblasts, both extravascular and intravascular may
be in mitosis. The capillaries and venules may become ex-
464
H. E. JORDAN
panded into sinusoidal structures with fenestrated walls during this process of intravascular proliferation and differentiation. Such hemopoietic areas consist, then, of what appear
to be irregular cords of lymphoid tissue with a central capillary or sinusoid; both capillary lumen and enveloping lymphoid area may contain hemocytoblasts, erythroblasts and
normoblasts. I n later stages such cords become confluent,
giving the appearance of an area of red bone marrow.
Meanwhile the expanding erythrocytopoietic sinusoids have
acquired openings, giving direct communication between the
vascular lumen and the interlipocellular spaces, permitting
plasma to pass directly into the tissue spaces. This secondary
fenestration of the capillary wall is presumably the result of
mechanical factors incident to the adaptation of the relatively
restricted lumen to the expanding cellular content and adjustment between the connective tissue investing the blood
channels and the stroma of the adipose tissue. No evidence
of hemocytopoietic activity on the part of endothelium appears in this tissue. The hemocytoblasts have a n extravascu1ar origin; these cells arise from what appear to be small
lymphocytes. The lymphoid accumulations are in part small
and widely scattered. The available evidence does not permit
of a definite conclusion as to whether they represent exclusively cells transported by lymphatics o r whether they are i n
part in situ derivatives of the intercellular connective tissue.
Local proliferation accounts for part of the increase of this
tissue.
THE ORIGIN O F ERYTHROCYTES I N FATTY AREAS O F LYMPH NODES
The lymph nodes here under consideration are those from
the case of adenocarcinoma of the prostate in which the
lymphoid tissue of all but a small polar area has been replaced by tumor tissue. This relatively normal area of the
lymph node has, however, the appearance of hemal node tissue
in that the sinuses contain a variable amount of blood; and
it resembles bone marrow in that it embraces centrally much
fat and peripherally much erythrocytopoietic tissue, includ-
BLOOD F O I i M A T I O N I N A D I P O S E TISSUE
465
ing megakaryocytes. The process is the reverse of that described above, in cases where adipose tissue becomes converted into lympho-erythroid tissue; here lympho-erythroid
tissue changes into adipose tissue ; lymph node tissue changes
into hemal node tissue which suffers hypoplasia centrally and
subsequently aplasia.
A low power field shows peripherally a uniform moderately
compact lymphoid condition. This represents the original
cortical area. Adjacent to this area, centrad, the structure is
one of cords and sinuses, representing the peripheral portion
of the original medulla. The sinuses contain blood ; the medullary cords have a relatively loose texture in which the reticular
cells and fibers are conspicuous. The parenchyma consists
predominantly of small lymphocytes, with considerable numbers of intermingled larger lymphocytes, red blood corpuscles
and erythroblasts. The central arteriole of the cords is conspicuous. The walls of the corresponding venules and the
connecting capillaries have the appearance in places of being
continuous with the adjacent reticular tissue and so effecting open communication between these vessels and the extravascular tissue spaces. Passing still deeper centrad the adjacent area contains a few fat cells. These cells arise in the
cordal areas, presumably from reticular cells. The fat cells
increase in number, and this area has exactly the appearance
of adipose tissue undergoing erythroid metaplasia. The interlipocellular spaces are filled with hemocytopoietic tissue enveloping one or several axial blood vessels. The hemocytopoietic tissue includes hemocytoblasts, lymphocytes, megakaryocytes, erythroblasts, normoblasts, and many red blood
corpuscles.
Along the inner border of this area the red blood corpuscles
predominate, and at the center the tissue consists only of fat
cells and stroma, with the intercellular spaces filled with red
blood corpuscles. The appearance suggests a condition of
hemorrhage within a fatty tissue. However, in the light of
the series of successive stages above outlined, the condition
must be interpreted as one of local red cell formation; the
466
H. E. JORDAN
blood stasis is presumably the results of the dilatation of the
capillary bed into a sinusoidal structure with communicating
intercellular spaces.
T H E CHANGE FROM H Y P E R P L A S T I C TO H Y P O P L A S T I C MARROW I N
EARLY STAGES O F BONE DEVELOPMENT
The material here under consideration is the femur of the
human fetus and infant. Early stages in the development of
enchrondral bone supply important data regarding the relationship between blood vessels and the hemocytoblasts. The
cartilaginous primordium of any long bone early becomes
enveloped at the level of the future diaphysis (primary center
of ossification) by a sheath of periosteal bone. Through this
extend into the primary center of ossification buds of vascularized mesenchyme from the inner layer of the periosteum. The
extension of these osteogenic buds keeps pace with the formation of primary areolae in the diaphyseal portion of the bone.
The tissue constitutes the primary marrow, and each bud
includes, in addition to the reticular stroma and an axial
arterial and venous vessel terminally connected by capillaries, a variety of cells. Peripherally the cells which adjoin
remnants of calcified cartilage function as osteoblasts ; centrally the cells resemble small and large lymphocytes. The
latter are typical hemocytoblasts. Such hemocytoblasts invade the sinusoidal and capillary channels where they differentiate into erythrocytes ; extravascularly, certain hemocytoblasts differentiate into granulocytes. The outstanding facts
are: absence of any activity in the formation of hemocytoblasts on the part of the endothelium; origin of hemocytoblasts from the reticular stroma (mesenchyme) ; envelopment
of axial blood vessels by hemocytopoietic tissue ; invasion of
venous and capillary vessels by hemocytoblasts t o diff erentiate intravascularly into erythrocytes.
The earlier hemocytopoietic marrow occurs in the form of
cords and islets of uniformly compact texture. Subsequently
fat cells appear, differentiation products of reticulum cells,
and as their number increases in the diaphyseal region the
BLOOD FORMATION I N ADIPOSE TISSUE
467
marrow assumes an open looser texture. The hemocytopoietic tissue with its primitive vascular supply becomes compressed between adjacent fat cells. At this stage erythrocytes
and red corpuscles occur both intravascularly and extravascularly in these marrow cords. The appearance may be
interpreted in terms of a rupture of the capillary wall permitting passage of definitive cells into the intercellular spaces ;
or as the result of an extravascular differentiation of erythrocytes. On the basis of my observations I am led to conclude
that both interpretations are in part correct. The rapid development of fat cells in large numbers from the reticular
stroma produces traction upon the delicate walls of adjacent
capillaries and sinusoids and causes breaks in the endothelium, permitting direct intercommunication between vascular
lumen and interlipocellular tissue spaces. Thus endothelium
becomes continuous at these fenestra with reticular cells of
the stroma. Accordingly, hemocytoblasts which arise from
stroma in such regions are a t once in intimate relation with
plasma and under this stimulus differentiate into erythrocytes.
The net result of the development of fatty marrow as regards blood cell production is the establishment of direct communication between the so-called erythrocytogenic capillaries
and certain spaces of the reticular tissue. This constitutes a
reticulo-endothelium and is the source of the hemocytoblast s
which, when either within a thin-walled vessel where the blood
is relatively stagnant or closely associated with such an area,
develop into erythrocytes. Both reticular cells and hemocytoblasts are occasionally seen in mitosis. There is no evidence
of hemocytopoietic activity on the part of the endothelium.
HYPOPZASTIC MARROW O F T H E F E M U R O F THE CAT I N EARLY
STAGESOFRECOVERY
The material includes femoral marrow from normal, suprarenalectomized and cortin-treated cats. The tissues were
fixed with Helly’s fluid and stained with the eosin-azure combination of Giemsa. Seven days after removal of the suprarenals the marrow is practically aplastic. Three days after
468
H. E. JORDAN
treatment with cortin the marrow of these experimental animals may be widely in process of recovery. The details of
the complete process of restoration will be dealt with in a
separate study jointly with Dr. S. W. Britton, who carried
out the experimental work. The only matter of interest in
this connection concerns the initial stages of recovery from
the extreme hypoplastic condition. There is no indication
of endothelial activity in relation to the appearance of hemocytoblasts in the capillaries among the fat cells. The initial
hemocytoblasts in the hypoplastic areas have a triple origin.
They represent in part locally persistent intravascular hemocytoblasts, which subsequently proliferate and so produce
local aggregations which differentiate into erythrocytes. In
part they represent migrants from peripheral relatively
normal intravascular collections of hemocytoblasts. I n small
part they represent local differentiation products of cells of
the interlipocellular reticular connective tissue which by
mitotic proliferation produce extravascular hemocytopoietic
islands from which hemoblasts migrate into the axial capillary
channels.
Conditions in the marrow of young normal cats confirm the
above outlined findings. Sections of femoral marrow, while
compact and hyperplastic in the main, include areas of considerable extent in conditions of variable degrees of hypoplasia. Examination of large extents of active marrow of
presumably normal animals leads me to the conclusion that
as concerns particular areas hemocytopoiesis is a cyclic process. A certain area passes through a stage of intense activity
(hyperplasia) to one of exhaustion (hypoplasia) followed by
phases of gradual restoration. Related in some manner to
this cyclic functional process is a histologic feature characterized by the presence of what appear to be genuine
lymphoid nodules, composed chiefly of small lymphocyte-like
cells. The details of this relationship of lymph nodules and
lymphocytes to the hemocytopoietic process are reserved for
a separate study. Interest in this connection only centers on
the aggregations of interlipocellular hemocytoblasts and the
BLOOD F O R M A T I O N I N ADIPOSE TISSUE
469
endothelium of the associated axial capilliform sinusoids in
the hypoplastic marrow in early stages of restoration.
Considerable numbers of the hemocytoblasts, both extravascular and intravascular, are in mitosis. Occasional hemocytoblasts can be seen passing through the endothelial wall;
they have a dumb-bell shape with one lobe in the lumen of the
sinusoid, the other in the enveloping hemocytopoietic tissue.
The direction of migration is presumably lumen-ward.
Whether or no the endothelial wall is actually fenestrated, it is
clear that it offers no effective barrier against hemocytoblast
migration. Many instances can be seen of capillaries containing a row of three to six hemocytoblasts, one or several in
mitosis, but no unequivocal evidence appears that such hemocytoblasts are endothelial derivatives. Furthermore, many
instances appear of hemocytoblasts pressed against the endothelium of larger sinusoids and some of the hemocytoblasts
may be considerably flattened, but again clear evidence is
lacking that they may represent derivatives of endothelial
cells. The extravascular hemocytoblasts are nearly as active
in mitotic proliferation as those within the blood channels.
While an occasional reticular cell may be seen in mitosis in
these areas of active restoration, only extremely rarely and
uncertainly, is an endothelial cell seen in mitosis. Such rare
and dubious instances of endothelial cell proliferation seem
more reasonably to bear the interpretation of a method of
adjusting the wall of a capillary to its expanding content of
hemocytoblasts than as a method of origin of erythrocyte
ancestors.
DISCUSSION
The outstanding fact which emerges from this study of the
development of hemogenic cells in adipose tissue concerns the
origin of the ancestral hemocytoblasts exclusively in extravascular stromal areas ;the endothelium of the involved capillaries and sinusoids is hemopoietically inactive. The original
groups of cells have the appearance of small lymphocytes.
These may in large part represent migrants from adjacent
470
H. E. JORDAN
lymphatics, but the occurrence of what appear to be transitional stages suggests also some slight degree of origin from
local stromal cells. These small lymphocyte-like cells grow
to the size and acquire the features of typical hemocytoblasts.
These hemocytoblasts may undergo a certain amount of proliferation and may migrate into the adjacent capillary. Within
the blood channel the hemocytoblasts differentiate into
erythrocytes.
A comparison of this process of extramedullary blood formation with the normal process in active bone marrow reveals
an essential identity. I n transiently hypoplastic areas at
initial and early stages of transition to renewed activity hemocytoblasts are seen to accumulate in interlipocellular cords
with axial capillary vessels. Hemocytoblasts migrate into the
adjacent capillary or venous sinusoid where they diff erentiate into erythrocytes. Extravascularly the hemocytoblasts
differentiate into granulocytes and megakaryocytes.
I n an attempt to elucidate the common problem of hemocytoblast origin and sinusoid-tissue-space relationship the study
of early stages in the formation of marrow in enchondral ossification has contributed valuable data. Stages in the transformation of hyperplastic into hypoplastic marrow are at least
of equal value with those of reverse order, which are those
heretofore almost exclusively studied. If endothelium during
any stage of medullary hemopoiesis has erythrocytopoietic
capacity, it might reasonably be expected to be active during
the stages when marrow is first formed. One seeks in vain
for unequivocal evidence of endothelial erythrocytopoietic
capacity in primordial marrow. The blood vascular system of
the eruptive tissue is closed.
The hemocytoblasts arise from the mesenchyme of this tissue. They constitute compact masses between and enveloping adjacent sinusoids and capillaries. They migrate in part
into the lumen of these vessels to differentiate into erythrocytes ; in part they differentiate extravascularly into granulocytes and megakaryocytes. When fat cells make their appearance in this myeloid tissue in the area of the future fatty
BLOOD F O R M A T I O N I N ADIPOSE TISSUE
471
diaphysis they effect a separation of the originally continuous
cell masses into small interlipocellular groups, more or less
intimately interconnected by slender strands of hemocytoblasts. Since the reticular stroma from which the fat cells
develop and which supports the hemocytoblasts is in continuity with that supporting the capillaries and sinusoids,
traction is exerted upon the delicate endothelial wall as the
fat cells enlarge in size and increase in number to the end
that communication is established at certain points along the
sinus between its lumen and adjacent intercellular spaces.
When hemocytoblasts are differentiated from the reticular
tissue bounding such spaces they are directly in contact with
plasma from the sinus and accordingly in relation to the
stimuli under which differentiation into erythrocytes is effected. The reticular tissue involved in this process, in view
of its relation to capillary endothelium, constitutes a reticuloendothelium of the hemohistioblast variety. I n active red
marrow a considerable amount of erythrocytopoiesis is extravascular, in areas communicating with sinusoids.
The above is in close conformity with earlier descriptions
of the erythrocytopoietic process in mammalian marrow (van
der Stricht, 1892; Maximow, '10). The accuracy of these descriptions is challenged by Doan, Cunningham and Sabin
( '25) who report origin of megaloblasts (erythrogenic hemocytoblasts) only from endothelial cells of 'intersinusoidal
capillaries' in the marrow of the pigeon and the rabbit. Peabody ('26) reports similar findings in human femoral marrow
from a case of typhus fever. Our earlier study of the marrow
of the frog (Jordan and Baker, '27) led us to conclude in favor
of the origin of the red cell ancestor from reticular cells. The
histology of hypoplastic femoral marrow of the frog at initial
stages of return to activity indicates an extravascular origin
of lymphoid hemoblasts, namely, from reticular cells, and
communication between the lumen of the venous sinusoids and
adjacent intercellular spaces. The interlipocellular spaces of
our frog material correspond exactly with the so-called intersinusoidal capillaries of Doan, Cunningham and Sabin. India
472
H. E. JORDAN
ink injection of our material showed that these communicating
channels are double walled sacs enveloping fat cells and cannot with any degree of terminological propriety be designated
capillaries. Such areas in section frequently include a central
capillary or sinusoid, and this vessel may be more or less completely filled with hemocytoblasts and differentiating erythroblasts; but study of successive stages in the development of
such erythrocytogenic capillaries shows that the hemocytoblasts arise extravascularly and only secondarily invade the
adjacent sinusoid. I n many instances also the hemocytoblasts
of a particular capillary have been transported via the vascular route from adjacent hyperplastic areas. Peabody describes an identical relationship between intercellular hemocytopoietic tissue and axial capillary, examples of which are
numerous in my sections of femoral marrow of the cat, but
makes the forced and very improbable interpretation of a
“branching transition capillary transversing a widely dilated
intersinusoidal capillary. ’ ’ On the basis of detailed histological studies of various tissues from instances of extramedullary hematopoiesis in anemias Brannan (’27) states, after an
apparently sympathetic effort to interpret conditions in terms
of endothelial activity, that in one case “there was a suggestive relationship between the capillary endothelium of the
liver and the myeloblasts, but one could not say that the white
or red blood cells arose from the endothehum.” As the result
of very extensive experimental investigations, including injections with India ink, Drinker and Drinker ( ’30) decide, in
essential agreement with Maximow ( ’lo), that in active mammalian bone marrow the wall of the capillaries become transiently fenestrated for the admission from adjacent extravascular areas of groups of maturing erythrocytes.
BLOOD F O R M A T I O N I N ADIPOSE TISSUE
473
SUMMARY
1. The object of this investigation of blood formation in
fatty areas of various tissues, under certain normal, pathologic and experimental conditions, is t o determine the origin
of the erythrocyte ancestor, whether endothelial or stromal ;
and the relation of the sinusoid lumen to the tissue spaces,
whether the endothelial boundary is continuous or fenestrated.
2. Normal adipose tissue of the renal capsule is supplied
by a closed vascular system in the cat. Specimens injected
with carmine gelatin show a dense capillary network; the
mesh has a diameter approximately that of the fat cells and
many fat cells are almost completely encircled by one o r
several capillaries.
3. Extramedullary blood production in the adipose tissue
of the renal pelvis and certain lobules in the vicinity of tumorous lymph nodes, and fatty areas in certain hemal nodes, in a
case of metastatic adenocarcinoma from the prostate is an
apparently identical process. Cells, resembling small lymphocytes, accumulate in certain areas about capillaries, where
they may grow into typical hemocytoblasts. From these
extravascular aggregations of lymphoid cells, hemocytoblasts
migrate into the axial capillary where they differentiate into
erythrocytes. I n the extravascular areas occur in addition
to the dominant lymphocytes and hemocytoblasts, occasional
granulocytes, megakaryocytes and macrophages. Endothelium in these regions lacks erythrocytopoietic capacity.
4. Hypoplastic marrow, natural or experimental, during
early stages of recovery passes through steps essentially
identical with those through which adipose tissue passes when
it undergoes erythroid metaplasia. However, in addition to
local extravascular accumulations of hemocytoblasts, which
may secondarily invade the vascular channels, intravascular
hemocytoblasts represent in part also persistent local hemocytoblasts and in part migrants from peripheral relatively
hyperplastic areas. Hemocytoblasts from these three sources
proliferate within the capillaries and sinusoids and diff erentiate into erythrocytes. There is no unequivocal evidence of
endothelial contribution of hemocytoblasts.
474
H. E. JORDAN
5, The reverse of the progressive process from hypoplasia
to hyperplasia, especially in primordial marrow, supplies
important evidence regarding the source of the initial hemocytoblasts and the relation of the capilliform sinusoids of
marrow to the stromal tissue spaces. Such reverse process,
namely, from hyperplasia to hypoplasia in the primordial
marrow of the future diaphysis of the femur, shows that the
original vascular system of the eruptive tissue is closed, and
that the compact enveloping marrow is of local stromal origin.
Even in these earlier stages the endothelium gives no evidence
of hemocytopoietic activity. The hemocytoblasts are reticularcell (mesenchyme) derivatives. They secondarily migrate
into the capillaries and venous sinusoids where they differentiate into red cells.
6. When the fat cells accumulate in the areas where the red
marrow of the future diaphysis is changing into yellow marrow, the interconnections between the walls of the capillaries
and the supporting reticular cells from which the fat cells
develop exert tractions upon the delicate endothelial wall,
effecting thus local communication between the erythrocytopoietic capillaries and the stromal tissue spaces. When a
condition of hyperplasia supervenes in such regions the hemocytoblasts arising from reticular cells differentiate within
tissue space already in communication with the venous
sinusoids and the group of differentiating erythrocytes
becomes enveloped by a reticulo-endothelium.
BLOOD F O R M A T I O N I N ADIPOSE TISSUE
475
LITERATURE CITED
BRANNAN,
D.
1927 Extramedullary hematopoiesis i n anemias. Bull. Johns
Hopkins Hospital, vol. 41, pp. 104-136.
DOAN, C. A. 1922 The circulation of the bone marrow. Contributions t o
Embryology, no. 67, Carnegie Institution of Wash., pub. no. 377,
pp. 2 9 4 6 .
DOAN,C. A., R. S. CUNNINGHAM
AND F. R. SABIN 1925 Experimental studies on
the origin and maturation of avian and mammalian red blood cells.
Contributions t o Embryology, vol. 16, Carnegie Institution of Wash.,
pub. no. 83, pp. 165-226.
DRINKER,C. K., I(. R. DRINKERAND C. C. LUND 1922 The circulation in the
mammalian bone marrow. Am. J. Physiol., vol. 62, pp. 1-92.
JORDAN,
H. E., AND J. P. BAKER,JR. 1927 The character of the wall of the
smaller blood vessels i n the bone marrow of the frog, with special
reference to the question of erythrocyte origin. Anat. Rec., vol. 35,
pp. 161-183.
MAXIMOW,A. 1910 Die embryonale Histogenese des Knochenmarks der Saugetiere. Arch. f . mikr. Anat., Bd. 76, S. 1-113.
PEABODY,
F. W. 1926 A study of hyperplasia of bone marrow i n man. Am.
J. Path., vol. 2, pp. 487-502.
SABIN,
FLORENCE
R. 1928 Bone marrow. Physiol. Reviews, vol. 8, pp. 191-244.
VAN DEE STRICHT,0. 1892 Nouvelles recherches sur la genhse des globules
rouges et des globules blancs du sang. Arch. de Biol., T. 12, pp. 199344.
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