REVIEWHuman circulating monocytes as multipotential progenitors
Noriyuki Seta and Masataka Kuwana

Division of Rheumatology, Department of Internal Medicine,
School of Medicine, Keio University, Tokyo, Japan(Received for publication on February 27, 2007)(Revised for publication on March 22, 2007)(Accepted for publication on April 19, 2007)

Abstract. Circulating monocytes are believed to be committed precursors for phagocytes,
such as macrophages and dendritic cells. Recently, we have reported a primitive human cell
population called monocyte-derived multipotential cells (MOMC), which has a fibroblastlike morphology and a unique phenotype positive for CD14, CD45, CD34, and type I collagen. This novel cell type exhibits mixed morphologic and phenotypic features of monocytes,
endothelial cells, and mesenchymal cells. MOMC are derived from circulating CD14＋ monocytes, and their differentiation requires binding to fibronectin and exposure to one or moresoluble factors derived from peripheral blood CD14- cells. MOMC contain progenitors withcapacity to differentiate into a variety of non-phagocytes, including bone, cartilage, fat, skeletal and cardiac muscle, neuron, and endothelium. Recent studies by others have also described several distinct human cell populations that are originated from circulating monocytes and have capacity to differentiate into non-phagocytes. These observations together
indicate that circulating monocytes are more multipotential than previously thought. In addition, cell transplantation therapies using circulating monocytes are a potential approachfor tissue regeneration. (Keio J Med 56 (2) : 41－ 47, June 2007)
Key words: differentiation, monocytes, progenitor, regeneration

Introduction

cytes. Our recent discovery of a primitive cell population
termed monocyte-derived multipotential cells (MOMC)
supports a concept of the multipotential nature of circulating monocytes.5 This review summarizes current understandings of non-phagocytic differentiation potentials
of human circulating CD14＋ monocytes.

Circulating CD14＋ monocytes are originated from hematopoietic stem cells in the bone marrow and consist of
5 to 10% of circulating white blood cells in humans.
They are heterogeneous population in terms of surface
markers, phagocytic capacity, and differentiation potentials, but are committed precursors in transit from thebone marrow to ultimate sites of activity.1 Circulating
monocytes have capacity to differentiate into a variety ofphagocytes, including macrophages, dendritic cells, osteoclasts, microglia in the central nervous system, andKupffer cells in the liver.1- 4 Until recently, it has been
believed that the differentiation potential of monocytes isrestricted to cells possessing phagocytic capacity, whichfunction as phagocytes and/or specialized antigen-presenting cells. However, recent accumulating evidence indicates that circulating monocytes have potential to differentiate into variety of cell types other than phago-

Identification of MOMC
MOMC, previously called monocyte-derived mesenchymal progenitors (MOMP), are a human cell population with a fibroblast-like morphology, and have aunique phenotype positive for CD14, CD45, CD34, andtype I collagen.5 MOMC can be obtained in cultures of
peripheral blood mononuclear cells (PBMC) for 7 to 10
days on fibronectin-coated plastic plates in Dulbecco’s
modified Eagle’s medium supplemented with 10% fetal
bovine serum as an only source of growth factors.5 The
majority of adherent cells obtained in this culture have a

To whom correspondence should be addressed: Masataka Kuwana, M.D., Ph.D., Division of Rheumatology, Department of Internal Medicine, School of
Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan, E-mail: kuwanam@sc.itc.keio.ac.jp41

42

fibroblast-like morphology, which is apparently different
from that of macrophages and dendritic cells. Interestingly, these cells contain progenitors capable of differentiating along several distinct non-hematopoietic lineages.
By electron microscopic examination, MOMC represent mixed features of phagocytes (primary lysosomes
and cell surface projections like pseudopodia), mesenchymal cells (prominent bundles of intermediate filaments and small lipid droplets), and endothelial cells(rod-shaped microtubulated bodies). MOMC express hematopoietic and monocyte lineage markers, including
CD45, CD11b, and CD14. MOMC also show expressionof several stem cell markers, such as CD34 and CD105/
SH2, but lack expression of CD117/c-kit and CD133.
Endothelial markers CD144/VE-cadherin and vascularendothelial growth factor (VEGF) receptor type 1(VEGFR1)/Flt-1 are present on the surface of MOMC. In
addition, MOMC are positive for type I and III collagens, fibronectin, and vimentin, which are typically produced by cells of mesenchymal origin. These findings
clearly show that MOMC have mixed morphologic andphenotypic features of phagocytes, mesenchymal cells,
and endothelial cells. These characteristics are unique,and are not consistent with any other previously described cells derived from human peripheral blood.
MOMC appear to be originated from circulating monocytes because they are positive for monocytic markers.
In fact, appearance of MOMC in PBMC cultures wascompletely inhibited by the depletion of CD14＋ monocytes. To further confirm the monocytic origin of
MOMC, highly enriched CD14＋ monocytes that werepre-labelled with a green fluorescent dye were cultured
with unlabelled CD14- PBMC (predominantly lymphocytes) on fibronectin-coated plates.5 As expected, fluorescence-labelled cells exclusively showed a fibroblastic
morphology and expressed CD34, indicating that precursors for MOMC are present within circulating CD14＋
monocytes. Interestingly, MOMC differentiation was notdetected when monocytes were cultured alone on fibronectin or were cultured with CD14- cells on untreatedplates, indicating that CD14- cells and binding to fibronectin are both required for the differentiation frommonocytes to MOMC. On the other hand, the MOMC
differentiation was observed when CD14＋ monocytes
were cultured alone in the conditioned medium generated by culture of CD14- cells on fibronectin, suggesting
an important role of soluble factor(s) produced by
CD14- cells, rather than a cell-to-cell contact.
The number of MOMC increases during culture, but
cell expansion becomes slower after the fourth passage
and the cell proliferation stops beyond fifth passages, indicating that MOMC have the ability to self-replicate,but their lifespan is limited.5 We tried hard to establish
MOMC clones without any success, because of limited
proliferative capacity. This feature is apparently different

Seta N and Kuwana M: Monocytes as multipotential progenitorsfrom stem cells.
Differentiation potentials of MOMC
MOMC can differentiate into a variety of mesenchymal cell types in specific permissive culture conditions
principally developed for mesenchymal stem cells.5 The
induction treatment of MOMC in vitro resulted in the expression of genes and proteins specific for bone, cartilage, fat, and skeletal muscle. The differentiation of
MOMC into individual mesenchymal cells followed thesteps observed in mesenchymal stem cell differentiation,in terms of the timing of lineage-specific transcription
factor expression. For example, expression of the myogenic transcription factor MyoD preceded the expressionof skeletal muscle actin and myosin. Our finding represented the first evidence that human circulating CD14＋
monocytes are a source of progenitors that exhibit mesenchymal cell differentiation.
In vitro differentiation of MOMC along the cardiomyogenic lineage required a co-culture with cardiomyocytes prepared from the embryonic rat heart.6 During thefirst 10 days of co-culture, the morphology of MOMC
changed from spindle-shaped to round and spread out,
and the majority of MOMC expressed the cardiomyocyte-specific transcription factors, such as Nkx2.5,
GATA-4, eHAND, and MEF2. After 2 weeks of co-culture with rat cardiomyocytes, MOMC gradually displayed a marked increase in surface area and became
multiangular morphology. Spontaneously beating
MOMC were observed after 3 weeks of the co-culture,albeit at relatively low efficiency (<5% of total MOMC).
These cells made contact with the surrounding rat cardiomyocytes and contracted in synchrony. At this stage,
MOMC expressed cardiomyocyte-specific structuralproteins, such asα-sarcomeric actinin and troponin I,
with typical staining patterns of the sarcomeric structures. In addition, MOMC expressed connexin43, a protein consisting of gap junctions, and ultimately formed
cell-to-cell contacts with the surrounding rat cardiomyocytes. Microinjection of the fluorescent dye into MOMC
revealed coupling as determined by direct dye transfer toneighboring rat cardiomyocytes. Cytoplasmic staining ofatrial natriuretic peptide (ANP), which is almost exclusively secreted by atrial cardiomyocytes, was observedin the perinuclear regions of MOMC. Expression of
CD45 and CD14 was gradually down-regulated during
cardiomyogenic differentiation and was lost when they
started spontaneous beating. An electrophysiologicalstudy revealed that contracting MOMC showed spontaneous periodic action potentials typical of cardiac myocytes. These observations clearly indicate that a certain
subset of MOMC is able to differentiate into cardiomyocytes of a mature phenotype with typical electrophysiological characteristics in vitro. The differentiation of

Keio J Med 2007; 56 (2): 41－ 47

MOMC into cardiomyocytes followed the steps observed in normal differentiation, in terms of the timingof lineage-specific transcription factor expression.
Subsequently, we demonstrated that human MOMC
can differentiate in vitro into the neuronal lineage using
the similar co-culture assay using primary cultures ofneuronal cells prepared from the embryonic rat brain.7
Within 3 days of co-cultivation, the vast majority of
MOMC showed nuclear expression of early neuroectodermal transcription factors, including Mash1, Ngn2,
and NeuroD. These transcription factor-positive MOMC
co-expressed nestin, an intermediate filament protein
expressed during neurogenesis.8 Over the next 2 weeksof the culture with rat neurons, a small population of
MOMC displayed a multi-polar neuron-like morphology. MOMC expressing neurofilament had numerous axon-like processes projecting long distances and formed
complex neural networks on the co-cultivated rat neurons. MOMC expressed β3-tubulin and MAP2, which
are known to be preferentially expressed by axonal processes in both shaft and spine synapses. In addition,these neuron-like MOMC also exhibited nuclear expression of the neuron-specific RNA-binding protein Hu andthe postmitotic neuron-specific nuclear protein NeuN.
At this stage, MOMC-derived neuron-like cells lost theexpression of CD45 and CD14. Again, the differentiation of MOMC into neurons followed the steps observedin normal differentiation; i.e. the expression of pro-neuronal transcription factors preceded the expression of
mature neuron-specific nuclear and structural proteins.
Taken together, a subset of MOMC is capable of differentiating along the neuronal lineage when placed into an
appropriate environment, although their differentiation
efficiency into mature neurons with typical morphologic
and molecular features was very low (<5% of the total
MOMC).
We recently reported that MOMC can differentiate into
endothelium of a mature phenotype with typical morphologic, phenotypic, and functional characteristics.9 MOMC
treated with a combination of angiogenic growth factors
for 7 days changed their morphology from spindleshaped to caudate, and these cells had numerous rodshaped microtubulated structures resembling WeibelPalade bodies. Almost every MOMC expressed endothelial markers, such as CD31, CD144, VEGFR1/Flt-1,
VEGFR2/KDR, Tie-2, von Willebrand factor (vWF), endothelial nitric oxide synthase (eNOS), and CD146, but
expression of CD14 and CD45 was markedly down-regulated. Functional characteristics, including vWF release
upon histamine stimulation and up-regulated expressionof VEGF and VEGFR1 in response to hypoxia, were indistinguishable between the MOMC-derived endotheliallike cells and cultured mature endothelial cells. MOMC
responded to angiogenic stimuli and promoted the formation of mature endothelial cell tubules in Matrigel®

43

cultures. Finally, in xenogenic transplantation studies using a SCID mouse model in which syngeneic colon carcinoma cells were injected subcutaneously with or without human MOMC, co-transplantation of MOMC significantly promoted the formation of blood vessels, andmore than 40% of the tumor vessel sections incorporated
human endothelial cells derived from MOMC. It is ofnote that MOMC expanded during endothelial differentiation. These findings together indicate that human
MOMC can proliferate and differentiate along the endothelial lineage in a specific permissive environment.
Multiple differentiation potentials of circulating
CD14＋ monocytes are summarized in Fig. 1. Monocytes
are long believed to be committed precursors specific forphagocytes, but our recent findings on MOMC indicatethat circulating monocytes have capacity to differentiate
into several distinct mesodermal and neuroectodermal
lineages through differentiation into MOMC, although it
is not known whether MOMC contain multipotent precursors or a group of monopotent precursors for several
distinct lineages. Efficiencies of differentiation in in vitro cultures are greatly variable among cell lineages: i.e.
high efficiency for endothelial and chondrogenic differentiation, but low efficiency for cardiomyogenic andneuronal differentiation. Differentiation from monocytes
to non-phagocytic cells may not be induced during normal development, but may be readily induced in thepresence of cues, such as massive tissue injury. Since thedifferentiation of monocytes into MOMC requires binding to fibronectin and soluble factor(s) from CD14 blood cells, circulating monocytes may encounter thesesignals at the site of tissue injury and inflammation. In
this scenario, circulating monocytes infiltrate into thesite of tissue injury and are exposed to fibronectin andsoluble factor(s) produced by infiltrating inflammatory
cells, resulting in their differentiation into MOMC. The
MOMC subsequently differentiate into tissue-specificcells in response to organ-specific cues provided by thesurrounding cells. By this process, monocytes may participate in tissue homeostasis by replacing differentiatedcells lost to physiologic turnover, injury, and senescence.
Circulating monocytes as endothelial precursors
In accordance with MOMC’s efficient differentiation
potential into the endothelial lineage, recent accumulating evidence indicates that circulating CD14＋ monocytes
serve as precursors for endothelial cells. Ultrastructuraland immunohistochemical studies in animal models
showed that monocytes accumulate within the vessel
wall of growing collaterals, suggesting that these cells
contribute to the process of vasculogenesis,10, 11 althoughsome recent studies showed that bone marrow-derived
hematopoietic cells are recruited to angiogenic region in
response to VEGF and contribute to vasculogenesis not44

Seta N and Kuwana M: Monocytes as multipotential progenitors

Fig. 1 Multiple differentiation potentials of circulating CD14＋ monocytes through differentiation into MOMC. *Vascular endothelial
growth factor, basic fibroblast growth factor (bFGF), epidermal growth factor, and insulin-like growth factor-1. **osteoblast,
dexamethasone, β-glycerophosphate, and ascorbic acid; chondroblast, TGF-β1; adipocyte, dexamethasone, methyl-isobutylxatine,
insulin, and indomethacin; and myoblast, pre-treatment with 5-azacitidine, following culture with horse serum, hydrocortisone, andbFGF.

Keio J Med 2007; 56 (2): 41－ 47

being integrated as endothelial cells, but existing outsideof vascular lumen.1 2 Fernandez-Pujol and colleagues
showed that, in the presence of angiogenic factors,
monocytes differentiate into endothelial-like cells expressing endothelial lineage markers, such as vWF,
CD144, CD105, and VEGFR2/KDR.1 3 Schmeisser andcolleagues reported that CD14＋ monocytes have potential to co-express endothelial lineage markers and monocytic antigens, and form tubular-like structures in threedimensional gel.14 In in vivo studies, it has been demonstrated that monocytes have the potential to be incorporated into the endothelium of co-lateral vessels and balloon-injured endothelium and to differentiate into endothelial cells.15-17
Asahara and colleagues first reported endothelial progenitor cells (EPC) obtained by culturing PBMC in media favoring endothelial differentiation, which were originally reported as circulating angioblasts.1 8 Migrationand homing of EPC to ischemic regions leads to de novo
formation of vascular structures: a process called vasculogenesis. Later, several investigator groups found thathuman EPC obtained by culturing PBMC are composed
predominantly of endothelial-like cells derived from circulating monocytes.1 9-2 1 In this regard, Hur and colleagues cultured PBMC under angiogenic stimuli and
identified two types of EPC.22 “Early EPC” with spindle
shape showed peak growth at 2 to 3 weeks and died after
4 weeks of the culture. On the other hand, “late EPC”
representing typical endothelial cobblestone appearance
became the dominant cell population after 4 weeks ofthe culture. Gulati et al reported similar findings. 2 3These reports suggested that the vast majority of early
EPC arise from CD14＋ monocytes, but late EPC develop exclusively from angioblasts within the CD14- fraction. Taken together, the majority of EPC are derived
from circulating CD14＋ monocytes. However, MOMC
were integrated into blood vessels and differentiated into
endothelium in vitro and in vivo more efficiently than
did freshly isolated circulating monocytes and monocytic EPC.9
Monocyte-derived cells with potentials todifferentiate into non-phagocytes
Until now, several distinct human cell populations thatare originated from circulating monocytes and have capacity to differentiate into non-phagocytes have been described. Zhao and colleagues demonstrated that pluripotent stem cells can be generated from a subset of peripheral blood monocytes by repeated stimulation with ahigh concentration of macrophage-colony stimulating
factor and phorbol myristate acetate.2 4 These spindleshaped CD34＋ cells termed pluripotent stem cells (PSC)
had the capacity to differentiate along several distinct
cell lineages: mature macrophages by stimulation with45

lipopolysaccharide, T lymphocytes by stimulation with
IL-2, epithelial cells by stimulation with epidermal
growth factor, endothelial cells by stimulation with
VEGF, neuronal cells by stimulation with nerve growth
factor, and liver cells by stimulation with hepatocyte
growth factor. It is interesting to mention that these authors successfully establish PSC clones from a single
cell, and confirm the ability of single PSC to differentiate into distinct cell lineages, further substantiating thepluripotent nature.
On the other hand, Romagnani and colleagues have reported that monocyte-derived EPC proliferate in response to stem cell growth factors, and exhibit multi-potency, as shown by their ability to differentiate not only
into endothelial cells, but also into osteoblasts, adipocytes, or neural cells.2 5 In this report, the authors argue
that monocytic EPC are originated from CD34low cells
within circulating CD14＋ monocytes. Low expression of
CD34 was not detectable by conventional flow cytometric analysis, but was detected using a highly-sensitive
antibody-conjugated magnetofluorescent liposome technique. The CD14＋CD34low cells exhibited clonogenicity
and high expression of embryonic stem cell markers,
Nanog and Oct-4. Unfortunately, we were unable to reproduce isolation of CD14＋CD34low pluripotent cells using a highly-sensitive flow cytometric technique.
In early 1990s, Bucala and colleagues described a population of circulating cells with fibroblast properties thatspecifically enter sites of tissue injury.26 This novel cell
type, termed fibrocytes, was characterized by its distinctive phenotype positive for CD45, CD34, and type I collagen by its rapid entry from blood into subcutaneously
implanted wound chambers. Fibrocytes contribute toscar formation and may play an important role both innormal wound repair and in pathological fibrotic responses. Fibrocytes are identified by characteristic phenotype positive for series of chemokine receptors, such
as CCR7, CXCR4, and CCR2.27, 28 Fibrocytes can be enriched by culturing PBMC on tissue culture plates coated with fibronectin or type I collagen for 14 days,26 but
Abe and colleagues recently found that human circulating CD14＋ monocytes in the presence of T cells gives
rise to fibrocytes.2 9 Therefore, circulating monocytes
possibly act as progenitors for fibroblasts to promote
physiologic or pathologic fibrosis.
Table 1 lists human monocyte-derived cells with potentials to differentiate into non-phagocytes. These
monocyte-derived cells commonly have spindle-shaped
morphology and express CD45 and CD34, but have several distinct characteristics. PSC and fibrocytes are able
to self-replicate and expand in long-term cultures,
whereas MOMC have limited lifespan like monocytic
EPC. In addition, generation of monocytic EPC and fibrocytes in PBMC cultures required either fibronectin ortype I collagen, but the MOMC induction culture using

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Seta N and Kuwana M: Monocytes as multipotential progenitors

Table 1 Cultured human cell populations that are originated from circulating monocytes and have capacity to differentiate into non-phagocytes

Morphology
CD14
CD45
CD34
Type I collagenLifespan
Cellular origin within
CD14＋ monocytes
Factors required for
differentiation frommonocytes
Differentiation potential

MOMC(Kuwana et al. 2003)
Spindle shape++++
Limited
Not identified

PSC(Zhao et al. 2003)
Spindle shape
+
+
+
N/D
Unlimited
Not identified

Monocytic (early) EPC

Binding to fibronectin
Soluble factors from CD14blood cells
Osteoblast
Skeletal myoblast
Chondrocyte
Adipocyte
Cardiomyocyte
Endothelial cell
NeuronA high concentration of
M-CSF and PMA

Binding to fibronectin or
Binding to fibronectin ortype I collagentype I collagen
Angiogenic growth factors T lymphocytes

Macrophage
T lymphocyte
Epithelial cell
Endothelial cell
NeuronHepatocyte

Osteoblast
Adipocyte
Endothelial cell
NeuronSpindle shape+++–
Limited
CD14＋CD34low(?)

Fibrocyte(Bucala et al. 1994)
Spindle shape–+++
Unlimited
CCR7＋CXCR4＋CCR2＋

Fibroblast
Myofibroblast

MOMC, monocyte-derived multipotential cells; PSC, pluripotent stem cells; EPC, endothelial progenitor cells; M-CSF, macrophage-colony
stimulating factor; PMA, phorbol myristate acetate.

type I collagen instead of fibronectin failed to generate
cells with multiple differentiation potentials (our unpublished data). Since cellular origins of these cell types
have not been fully identified yet, circulating precursors
within circulating CD14＋ monocytes may be different.
Alternatively, distinct differentiation potentials of theseprimitive cells might be due to different culture conditions of the same precursors.
Summary and conclusions
We have now several lines of convincing evidence
showing that circulating CD14＋ monocytes have the potential to differentiate into various non-phagocytes, including mesodermal and neuroectodermal lineages. In
1867, Cohnheim described that peripheral blood monocytes participate in the normal tissue renewal of variousorgans.3 0 This investigator probably reached the rightconclusion too early according to the times of science.
These observations challenge the traditional view of thebiology of the monocyte/phagocyte system. We believethat it will lead to further progress in the understandingof the differentiation potential of monocytes and theroles they play in the physiology of health and disease.
On the other hand, cell replacement therapy may becomea useful approach for repairing the lethally damaged tissue. A variety of cell types have been proposed as transplantable cells for tissue regenerative therapy, but themulti-potentiality of circulating cells has been underestimated to date. Cellular therapy using primitive cells derived from circulating monocytes has considerable ad-vantages over the currently proposed strategies using tissue-specific stem cells and embryonic stem cells, since
circulating monocytes would be a relatively obtainablesource of autologous cells. Among these primitive cells,
MOMC can differentiate into a variety of cell types
across lineages. However, further in vivo studies evaluating whether the transplantation of monocyte-derived
primitive cells such as MOMC promote regeneration in
the damaged tissues are necessary to confirm their potential use in cell therapy.
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