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Stem cell homing: From physiology to therapeutics
Jane L. Liesveld, Naman Sharma, Omar S. Aljitawi
Received: 30 December 2019 Accepted: 24 May 2020
DOI: 10.1002/stem.3242

CONCISE REVIEW

Stem cell homing: From physiology to therapeutics

Jane L. Liesveld | Naman Sharma | Omar S. Aljitawi

James P. Wilmot Cancer Institute, Department

Abstract

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of Medicine, University of Rochester,
Rochester, New York Stem cell homing is a multistep endogenous physiologic process that is also used by
Correspondence exogenously administered hematopoietic stem and progenitor cells (HSPCs). This
Jane L. Liesveld, MD, Wilmot Cancer Institute, multistep process involves cell migration and is essential for hematopoietic stem cell
601 Elmwood Avenue, Box 704, Rochester,
NY 14642. transplantation. The process can be manipulated to enhance ultimate engraftment
Email: jane_liesveld@urmc.rochester.edu potential, and understanding stem cell homing is also important to the understanding
of stem cell mobilization. Homing is also of potential importance in the recruitment
of marrow mesenchymal stem and stromal cells (MSCs) to sites of injury and regener-
ation. This process is less understood but assumes importance when these cells are
used for repair purposes. In this review, the process of HSPC and MSC homing is
examined, as are methods to enhance this process.

KEYWORDS

cell migration, hematopoietic stem cells, homing, mobilization, mesenchymal stem cells,
mesenchymal stromal cells

1 | I N T RO DU CT I O N tissue in need of repair. The process of homing is therefore of impor-

tance to normal hematopoiesis, transplantation, regenerative thera-
Stem cell homing refers to the ability of circulating stem cells or exog- pies, and in the migration of leukemia cells to extramedullary sites.
enously administered stem cells to locate and enter an environmental In vitro assays to study homing have used chamber or transwell
niche. Throughout its life span, a stem cell may migrate between systems to study rolling and migration.1,2 In vivo assays can involve
niches during embryonic development and also during the adult cell labeling for tracking purposes, intravenous injection, and imag-
life span. In the case of marrow mesenchymal stem cells, homing to ing or harvest in 24 hours to see what fraction has homed to mar-
injured tissues may also occur. This review will focus on homing of row or tissue of interest. Stem cell transplantation is the most
both hematopoietic stem/progenitor cells (HSPCs) and of mesenchy- examined in vivo model of stem cell homing, and in that case, hom-
mal stem/stromal cells (MSCs). The former is the best studied stem ing efficiencies are not optimal. When homing efficiency has been
cell as relates to homing since stem cell transplantation is reliant on determined by injection of limiting dilutions of progenitors into
this process. Hematopoietic stem cells (HSCs) have self-renewal and lethally irradiated immunocompetent mice, the homing efficiency as
multipotential differentiation capability and can be defined by expres- measured by spleen colony forming units and cobblestone area for-
sion of various surface markers. Homing studies have focused on ming cells is about 20%,3 and when sorted human CD34+ cord
CD34+ stem and progenitor cells as this is the population quantified blood progenitors are injected into nonobese diabetic/severe com-
for human HSC transplantation purposes. MSCs are plastic adherent bined immunodeficiency (NOD/SCID) mice, only about 2.5% of cells
cells which express CD73, CD105, and CD90 without expression of are estimated to home to the bone marrow based on flow cytometry
other lineage markers. They have capacity to differentiate into osteo- analysis of bone marrow cells harvested from a femur at 24 hours.4
blasts, adipocytes, and chondrocytes. Homing of MSCs is thought to These studies of homing efficiency suffer from starting population
be important in tissue regeneration which reflects the ability of heterogeneity3 or a murine microenvironment,4 so true engraftment
recruitment and homing of stem and progenitor cells to the damaged efficiencies of human HSPCs are not well understood. The efficiency

Stem Cells. 2020;38:1241–1253. wileyonlinelibrary.com/journal/stem ©AlphaMed Press 2020 1241

1242 LIESVELD ET AL.

of stem cell homing to marrow can also be influenced by accessory

cells such as T lymphocytes which modulate chemokine and cyto- Significance statement
kine expression.5
Stem cell homing is essential for successful hematopoietic
stem cell transplantation, so understanding how to enhance
and refine it has clinical significance. Examination of the
2 | S T E M C E L L M I G R A T I O N D U RI NG
homing of mesenchymal stromal cells to sites of tissue injury
E M B R Y O G EN E S I S
has assumed importance as these cells are now being used
increasingly in therapeutic settings.
Human HSCs arise from endothelium associated with blood vessels in
both embryonic and extra-embryonic sites which include the dorsal
aorta, the umbilical and vitelline arteries, the yolk sac, and the pla-
centa.6,7 Hematopoiesis occurs first in the yolk sac, later in the fetal sinuses collect into large central sinuses which empty to the sys-

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liver and possibly spleen, and subsequently in the bone marrow at the temic circulation via emissary veins.14
time of birth. Major expansion in stem cell numbers occurs in the fetal The cellular components in the hematopoietic areas of the mar-
8
liver. Cavities within bone begin to form at about the fifth fetal month row also include nonhematopoietic cells such as sinusoidal endothelial
and these become exclusive sites for granulocytic and megakaryocytic cells and MSCs which can differentiate into chondrocytes, osteo-
proliferation, but erythrocyte proliferation occurs in marrow only during blasts, osteocytes, fibroblasts, and adipocytes.12 Osteoclasts are also
the last gestational trimester. The migration of HSCs to these marrow present. In addition, terminally differentiated cells of hematopoietic
cavities occurs in response to chemokines such as CXCL12 (also origin such as macrophages, lymphocytes, and plasma cells constitute
referred to as stroma derived factor-1α), but the angiopoietin, Notch parts of the hematopoietic niche and may be sources of cytokines and
and hedgehog pathways are also involved. The mechanisms that ini- chemokines involved in stem cell homing.12 These include CXCL12, c-
tially attract HSPCs to the fetal liver and then allow egress for marrow kit ligand (stem cell factor), vascular endothelial growth factor 2
6,9
seeding remain unknown. Studies in the caudal hematopoietic tissue (VEGF2), and pleiotrophin.12
of zebra fish where stem cells can be easily tracked and which is equiv- Hematopoiesis occurs in extravascular spaces between marrow
alent to mammalian fetal liver stages have shown that a vascular cell sinuses. The wall of the marrow sinus is composed of a luminal layer
adhesion molecule-1 (VCAM-1) expressing macrophage like cell in the of endothelial cells and an incomplete outer lining of adventitial retic-
niche patrols the inner surface of the venous plexus and interacts with ular cells. The sinusoidal endothelial cells express type IV collagen and
HSPCs in an integrin (ITG)A4-dependent manner. This allows HSPC laminin basement membranes and various adhesion molecules such as
retention and eventual homing to a vascular niche.10 In zebra fish as in integrins and selectins which are involved in cell trafficking. They also
mammals, HSPCs migrate through various niches during development. secrete cytokines such as c-kit ligand and express CD44 ligands which
Models such as zebra fish with easy labeling and tracking of stem cells are involved in homing of HSPCs.17 The arteriolar endothelial cells are
may therefore provide valuable information about physiologic stem cell thought to maintain HSPCs in a low reactive oxygen species (ROS)
migration and homing since factors guiding these processes have been state, whereas the permeable sinusoids promote HSPC activation and
difficult to discern in mammalian systems. In mammals, one of the main are the site for leukocyte trafficking to and from the marrow.18 Expo-
obstacles to generating HSCs from pluripotent stem cells is maintaining sure to blood plasma had been found to increase HSPC ROS levels.18
11
and enhancing their homing efficiency. This may contribute to stem cell proliferation, differentiation, and
eventual egress near the sinusoidal endothelial cells. The adventitial
reticular cells secrete CXCL1219 and c-kit ligand20 which maintain
3 | THE BONE MARROW NICHE HSPC lodgment near the marrow sinusoids through CXCR4 and c-kit
interactions. In normal hematopoiesis, marrow resident HSPCs are
The marrow niche is the local tissue and chemical environment in retained in the extravascular spaces where they proliferate and differ-
which HSCs reside, proliferate, and differentiate. It is the lodging entiate into mature elements which move across the sinus endothe-
place to which homing occurs and the site from which migration lium and circulate into blood. At baseline, low numbers of HSPCs
and egress occur. The niche is generally described as having both circulate in blood. These cells quickly circulate back to marrow or may
vascular and endosteal components, but this is much more contribute to extramedullary hematopoiesis in pathological states.21
established in murine than in human marrow.12 Sympathetic nerves Mesenchymal stromal cells create a network of extracellular
13
enervate the niche. The blood supply to the marrow comes matrix proteins such as proteoglycans/glycosaminoglycans, fibronec-
mainly from the nutrient artery which penetrates the nutrient canal tin, collagens, laminin, and thrombospondin.22 The matrix can serve as
and then bifurcates into ascending and descending central medul- a reservoir for growth factors, and it provides noncellular ligands such
lary arteries. This generates radicular branches which join perios- as fibronectin, laminin, collagen, osteopontin, hyaluronan, and peri-
14
teal capillaries in the canalicular system. Cortical capillaries ostin for surface adhesion molecules on HSPCs and MSCs which are
eventually enter the marrow cavity proper and form a sinusoidal important for homing and retention. HSPCs may also reside in the
network. Most HSCs localize to sinusoidal blood vessels.15,16 These endosteal niche where there is abundant production of CXCL12 by
STEM CELL HOMING 1243

osteoblasts and osteoclasts.23,24 Stem cell retention in the endosteal function-associated antigen-1; CD11a) on the HSPCs.35 HSPCs also
niche is also facilitated by calcium receptors and the Tie2 receptor, express several other adhesion molecules such as L-selectin (CD62L)
25
which is necessary for binding to collagen and fibronectin. Cyto- which binds GlyCAM-1 (glycosylation dependent cell adhesion mole-
kines such as thrombopoietin are also produced by the osteo- cule), MAdCAM-1, P-selectin glycoprotein ligand-1 (CD162; PSGL-1),
blasts.26,27 Thrombopoietin plays a role in maintaining adult stem cells CD34, sialyl Lewisx (sLex), and PCLP1 (podocalyxin-like protein).36 The
in a quiescent G0 state. The endosteal niche is often considered as P (CD62P)- and E-(CD62E) selectins are expressed on the surface of
important for long-term HSPC maintenance through induction of stem the endothelial cells. P-selectin binds to CD162, sLex, and CD24, and
cell quiescence. Transplanted HSPCs are thought to ultimately lodge E-selectin binds to CD15, SLeX, CD162, and other ligands. Interac-
5
primarily in the endosteal niche. tions with selectins allow the leukocytes to roll on the endothelial sur-
face after which adherence and tethering occur. The initial binding of
stem cell integrins to endothelial ligands is weak, but CXCL12 and c-
4 | HSPC HOMING: ROLLING, ADHESION, kit ligand signaling interactions trigger conformational changes in

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A N D TR A N S M I G R A T I O N these integrins which foster further rolling and adhesion interactions
as well as cytoskeletal changes. The VLA-4–VCAM-1 (CD49d/
Under normal states in adult humans, hematopoiesis occurs in mar- CD106) interaction has prime importance in homing,37 and
row, and immature blood elements do not exit marrow. Precursor α5β1,α4β7, α1β2 and α6 integrins may also contribute independently
cells, such as blasts, promyelocytes, and myelocytes, are rarely to homing.38
observed on blood smears, and while erythroid colony forming units Once rolling and adhesion of the HSPC occurs, the expression of
(CFU-Es) and megakaryocyte colony forming units (CFU-Megs) can be VCAM-1, ICAM-1, and E- and P-selectin on marrow sinusoidal endo-
cultured from blood, megakaryocyte elements and nucleated red cells thelium is upregulated to facilitate the tethering process.39 Unlike the
are not observed. Reticulocytes are passively released, and erythro- case in other vascular beds, E-selectin is constitutively expressed by
poietin results in marked reduction in adventitial cell barriers, thus marrow endothelial cells. After tethering and adhesion, the cell must
28
facilitating egress. Podosomes and proplatelets extend through the then penetrate through the endothelial cell cytoplasm or through cell-
sinusoidal endothelium, and platelet release occurs through sheer cell junctions. Both murine and human HSPCs are able to form
force from blood flow.29 Despite those observations, a small percent- podosomes which allow direct transcellular migration, but in condi-
age of HSPCs are continuously entering the systemic circulation tions where vascular endothelial cadherin function is lost, increased
through the venous sinusoids and re-entering the marrow after brief permeability and paracellular migration can occur.40 They then
circulation. This physiologic rehoming is a process whose role is ampli- migrate between adventitial cells to the final place of lodgment. This
fied in settings of stem cell transplantation where intravenously relies on intrinsic amoeboid migratory ability of stem cells and inva-
injected stem cells must enter the marrow to establish hematopoiesis. sion by means of matrix degradation which occurs as a result of secre-
The role of physiologic stem cell migration is not fully understood but tion of matrix metalloproteinases MMP-2 and MMP-9 by the
could be a protective mechanism in case of severe marrow injury or HSPCs.41 Some HSCs lodge near arterioles which are thought to
may be a response to subclinical inflammatory signals from remote tis- maintain a low reactive oxygen species environment (ROSlo) whereas
sues.21 Such physiological mobilization also has a circadian rhythm stem cells near the sinusoidal endothelial cells have higher levels of
with peak circulation 5 hours after light exposure and nadir 5 hours ROS. High ROS can contribute to differentiation and mobilization
after darkness.30 whereas ROSlo states lead to quiescence and self-renewal.42 CD44
The first step in homing of HSPCs to marrow is interaction with and hyaluronic acid cooperate with CXCL12 in the transendothelial
the sinusoidal endothelium. Endothelial cells direct HSPCs to the mar- migration and in the final lodgment within the marrow.43 Marrow
row and slow cell movement under the shear stress of blood flow so laminins can also influence progenitor cell cycling and homing to the
that the HSPC can tether to and roll along the endothelium.31 The marrow. Laminin α4, α3, and α5 isoforms are all present, and laminin
shear stress is lower in sinusoidal vessels which aids the homing pro- 421 (α4β3Υ1) is a major component44 and is located near venous
cess. Homing of HSPCs requires selectin receptors with galactosyl sinuses and in close association with HSPCs in murine marrow. Fig-
32
and mannosyl specificities. Loss of function studies have shown that ure 1 illustrates the proposed steps in homing for HSPCs.
homing to the marrow niche is impaired with both P- and E-selectin CXCL12 and its receptors, CXCR4, and CXCR7 are involved in
deficiencies.33,34 homeostatic maintenance of HSPCs and their progeny in the marrow,
After selectin-mediated braking, HSCs migrate on adhesion and the CXCL12/CXCR4 axis is probably the prime governance of
ligands presented by the vascular endothelium. These include ligands stem cell homing and engraftment after human transplantation.45
for CD49d-f, CD11b, and CD11c such as vascular cell adhesion mole- CXCL12 is expressed by marrow stromal cells and endothelial cells.
cule-1 (CD106; VCAM-1), fibronectin, laminin, mucosal vascular The migration of human CD34+ HSPCs toward a CXCL12 gradient
addressin cell adhesion molecule 1 (MAdCAM-1), and intercellular in vitro has been shown to correlate with engraftment in immune
adhesion molecule-1 (CD54; ICAM-1). The stem cells have to migrate deficient mice and patients.45 Upregulation of CXCR4 via c-kit ligand
against the direction of blood flow, and through antibody blocking and IL-6 results in increased homing and repopulation of the marrow
studies, this has been found to be dependent on LFA-1 (lymphocyte niche.41,46 Pretreatment of HSPCs with CXCL12 in vitro will increase
1244 LIESVELD ET AL.

F I G U R E 1 Steps in HSC homing

and egress to and from marrow.
Homing (left) occurs in the marrow
sinusoidal endothelium. (1) Selectin-
mediated braking or rolling occurs.
Selectins involved include P-selectin
which interacts with CD162, SLex,
and E-selectin which recognizes
CD15, SLex, and CD162 on stem
cells. (2) HSCs migrate on adhesion
ligands presented by the vascular
endothelium, so-called tethering. This
involves CD49d-f, CD11b, and
CD11c on the HSPCs and CD106/

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fibronectin, laminin, and ICAM-1 on
endothelium as well as numerous
other adhesion receptors and their
ligands. (3) Changes in integrin
conformation facilitate tight adhesion
to the endothelial cell. (4) The stem
cell then migrates through the
endothelial cell cytoplasm or
paracellularly. The cell will then
migrate through matrix to reach the
lodging destination. This is facilitated
by CXCL12, c-kit ligand, cathepsins,
and matrix metalloproteinases. Egress
(right) involves: (1) Matrix
transmigration in response to
chemokine and growth factor effects.
Matrix components involved include
collagen IV, laminin, fibronectin,
hyaluronic acid, and tenascin; among
others. (2) Trans-endothelial
migration, and (3) Cell release with
disruption of receptor/ligand
interactions such as those between
CXCL12 and CXCR4 or CD49d and
CD106 (VCAM-1). HSC,
hematopoietic stem cell; HSPC,
hematopoietic stem and progenitor
cell; ICAM-1, intercellular adhesion
molecule-1

engraftment of these cells in immune deficient mice possibly through as S1P and ceramide-1-phosphate, both of which can function as
upregulation of CXCR441 or via affecting HSPC cell cycle status.47 chemoattractants for HSPCs.50
This axis is also important in stem cell retention in marrow, so it is In addition to the CXCL12/CXCR4 axis, there is also evidence in
likely that concentration gradients of CXCL12 and HSPC CXCR4 murine models that CD82, a tetraspanin, aids in regulation of HSPC
expression levels are important in determining site of stem cell resi- maintenance, homing, and engraftment. In CD82 knockout mice,
dence. The CXCL12/CXCR4 axis may also interact with the α4/VCAM HSPCs from the knockout exhibited stem cell migratory and spreading
axis to enhance homing as noted above.48 Sphingosine-1 phosphate defects. This was found to be related to hyeractivation of Rac 1
(S1P) is a bioactive lipid which is also involved in HSPC homing and GTPases in these CD82 knockout HSPCs since Rac1 inhibition res-
engraftment. Mice deficient in sphingosine kinase 1 demonstrate cued homing capacity.51
defective homing and engraftment by normal HSPCs and especially
by HSPCs from mice with conditional deletion of CXCR4.49 When
marrow is lethally irradiated, a proteolytic state results which activates 4.1 | Homing and retention of malignant cells
the membrane attack complex of the complement cascade and simul-
taneously impairs the chemotactic activity of CXCL12. This is com- The same processes which affect normal HSPC homing can also affect
pensated for by increases in proteolysis-resistant bioactive lipids such leukemia stem cell migration and homing to extramedullary tissue
STEM CELL HOMING 1245

niches or their return to marrow where they can pirate the normal also been demonstrated to lead to progression of MLL-AF9 and other
hematopoietic niche.52 These leukemia initiating cells often circulate leukemias. TWIST1 is a highly conserved transcription factor, and this
along with leukemia blasts. In pathologic extramedullary hematopoie- model suggests that certain microenvironmental factors have diverse
sis, there is evidence that the CXCL12/CXCR4 axis is involved in effects on normal and leukemia stem and progenitor cells.63
recruitment of leukemia HSPCs. For example, liver sinusoidal endo- In chronic leukemias, cell homing mechanisms can also be of
thelial cells are a source of CXCL12 which can attract extramedullary importance in disease propagation. In a murine CML model, CD44 on
hematopoietic cells.53 CXCR7 has also been found to contribute to leukemia cells and E-selectin on marrow endothelium were found to
homing of acute myelogenous leukemia (AML) progenitor cells to mar- be mediators of engraftment. CD44 and CD44 variants contributed to
row and spleen of NOD/SCID mice in response to CXCL12.54 β3 not only normal but also leukemia-initiating cell homing to and main-
integrins are also involved in the homing of xenografted primary tenance within the niche. This relates to its interaction with adjacent
human AML cells. 55
The β3 integrin (ITGB3) chain forms heterodimers cells and with the hyaluronan receptor.64 Treatment with the E-
with αIIb and αV exclusively. This integrin class is important for the selectin inhibitor GMI-1271 in combination with imatinib prolonged

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binding of leukemia cells to vitronectin and fibronectin. These effects the survival of mice engrafted with human CML initiating cells, and
are mediated through activation of Syk kinase.55 this was associated with decreased contact time of leukemia cells with
The role of the sinusoidal endothelium in egress of leukemia cells the marrow endothelium. This nonadhesion led to an increase in cell
is not completely understood, but vascular density is increased in cycle progression and an increase in expression of the SCL/Tal1 proto-
AML marrow.56 Under normal conditions, the passage of myeloid cells oncogene in leukemia-initiating cells.65 Increased SCL/TAL1 expres-
is restricted to neutrophils and bands, but in AML the selectivity of sion was also associated with improved outcome in human CML.65 In
the egress is disturbed. Furthermore, leukemia blasts and stem/pro- a murine CML model (SCL-TTA/BCR-ABL transgenic inducible CML),
genitor cells invade various tissues and organs preferentially, so study- targeted deletion of CXCL12 from MSCs reduced normal HSC number
ing microvascular endothelial-leukemia cell interactions is important but allowed leukemia stem cell (LSC) expansion through Ezh2 activity.
to understanding aberrant egress and extramedullary homing. AML However, when endothelial CXCL12 was deleted, decreased LSC pro-
blasts express CD44, VLA-4, CD117, and CXCR4, all of which are liferation was noted, suggesting niche-specific effects.66 If MSCs were
thought to be of importance in AML stem cell homing and egress. Gal- depleted of CXCL12, LSCs could be more effectively eliminated by
ectins are a family of β-galactosidase binding proteins which may also tyrosine kinase inhibitor therapy.66
impact leukemia initiating cell mobilization and homing. Galectin 1 and When other tumor types such as breast or prostate carcinomas
3 (LGALS1 and LGALS3) are thought to influence cell adhesion and metastasize to bone, their homing via sinusoidal endothelial cells
cell-cell interactions in the leukemia niche.57 Alteration in expression which regulate trafficking are thought to use similar mechanisms as
of these molecules may lead to egress and may impart survival advan- leukemia cell homing.67
tage after homing to extramedullary sites.58,59
Why leukemia cells are attracted to certain vascular beds such as
those of skin and central nervous system and not others is not well 5 | S TE M C EL L M O B I LI Z A TI O N
understood; whether inflammatory alteration of vessel permeability or
induction of enhanced selectin and integrin expression plays a role is The term stem cell mobilization is usually used to refer to induced
unclear. Local chemokine modulation in target tissues may also attract mechanisms of cell egress from the marrow. Marrow sinusoidal endo-
leukemia blasts and leukemia stem cells. thelium is a regulator of cell egress from the marrow just as it is
Leukemia blasts interact with selectins expressed by vascular important for homing.68 Marrow cell mobilization into the peripheral
endothelium and these interactions promote drug resistance and blood takes place in regions where the adventitial cells are absent,
leukostasis. For rolling, myeloblasts have been found to primarily and the barrier is just the sinusoidal endothelium. Egress is tran-
interact with P-selectin via PSGL-1 and with E-selectin via PSGL-1 scellular where the cytoplasm of sinusoidal endothelial cells is
and CD44.60 Lymphoblasts, in contrast, interact with E-selectin mainly thinned.69 Marrow sinusoidal endothelial cells are involved in egress
through CD43 and /or CD44.60 Cytokines secreted by blast cells may through adhesion molecules, chemokines, and MMP-9. The basement
increase the expression of E- or P-selectin on endothelial cells and membrane proteins, collagen type IV and laminin, are subject to
enhance their recruitment into extramedullary tissues which could effects of the metalloproteinases and elastases with resultant migra-
lead to leukostasis.60 Once homed, these blasts may have survival and tion and egress.70
drug resistance mediated by their E-selectin interactions.61 In AML, Stem cells that have mobilized from marrow to blood are used as
trials with E-selectin inhibitors and with CXCR4 inhibitors are ongoing the graft source almost exclusively in autologous stem cell transplan-
or have completed early phase testing. These inhibitors are used in an tation (reviewed in Reference 71), and they are also used in a majority
attempt to induce a chemosensitive state after disruption of leuke- of related and unrelated allogeneic stem cell transplants in adults as
mia-endothelial cell interactions.61,62 Various transcription factors can compared with marrow stem cells. There is always a baseline stem cell
also affect homing status of normal and malignant stem cells. For egress as previously noted.21 Depletion of Nestin positive MSCs
example, deletion of Twist-1 in murine marrow reduces normal HSPC increased this baseline mobilization as did adrenergic firing of the
homing and retention as well as self-renewal, but such knockout has sympathetic nervous system.72 Granulocyte colony stimulating factor
1246 LIESVELD ET AL.

(G-CSF) is the most commonly used pharmacologic agent to cause TABLE 1 Methods to enhance hematopoietic stem cell homing
mobilization, and it works through myeloid compartment expansion, Method Mediator(s) Reference
neutrophil elastase activity, cathepsin G release, and through decrease
Stromal cell coculture to CXCL12/ 81-85
in CXCL12 levels.73 Plerixafor, a CXCR4 inhibitor, can also result in increase HSPC CXCR4 endothelial cells
rapid stem cell mobilization due to rapid cleavage of binding to expression
CXCL12. It was first developed as an HIV virus entry inhibitor and Modulation of CXCR4/CXCL12 PGE2/HDAC 86-89
was noted to increase white cell count. It reversibly blocks CXCL12- to increase HSPC CXCR4 inhibitors
expression
CXCR4 binding, and it is approved with G-CSF for stem cell mobiliza-
tion in multiple myeloma and non-Hodgkin lymphoma.74 Other Fucosylation of selectin ligands Fucosyltransferases 90,91

CXCR4 inhibitors have also entered clinical trials (reviewed in Refer- Erythropoietin receptor Hyperbaric oxygen 92-95
modulation on HSPCs
ence 71).
Other agents which lead to stem cell mobilization include SIP-1 CD26 cleavage of CXCL12 Diprotin A/ 96-98

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sitagliptin
inhibitors which can be affected by complement levels, especially C5
Modulation of ROS levels S1P 50
mediated proteolysis.75 Cobalt protoporphyrin IX has been shown in
murine models to mobilize higher numbers of HSPCs and mature Abbreviations: EPO-R, erythropoietin receptor; HDAC, histone
granulocytes than does G-CSF.76 VCAM/VLA-4 inhibitors result in deacetylase; HSPC, hematopoietic stem and progenitor cell; PGE2, prosta-
glandin E2; ROS, reactive oxygen species; S1P; sphingosine-1-phosphate.
stem cell mobilization, and small molecule inhibitors of this axis are
being tested, often in combination with plerixafor.74 Stem cell mobili-
zation will also occur during the marrow recovery phase after chemo- (CD34+ human cord blood cells). This was thought to be mediated by
therapy administration along with G-CSF. Cyclophosphamide has increased expression of CXCR4 on CD34+CD38− cells.101 When
often been used with G-CSF for stem cell mobilization purposes, and MSCs are primed with nitric oxide, this enhances engraftment of
chemotherapy or radiation exposure may increase marrow hypoxia. cocultured HSCs through the intercellular transfer of microvesicles
Stabilization of hypoxia inducible factor-1α (HIF-1α) increases mobili- with messenger RNAs supportive of HSCs.102 Ex vivo coculture with
zation through vasodilatation of sinusoids due to increased VEGF porcine umbilical vein endothelial cells can enhance autologous CD34
levels, with resultant increase in mobilization. FG-4497 is a molecule + cell engraftment and reconstitution in vivo in a baboon model.103
which stabilizes HIF-1α and has been examined in mice with G-CSF Primary human marrow endothelial cells can also be cultured in vitro
and plerixafor for stem cell mobilization. This agent inhibits propyl in specified media conditions. These cells can also promote engraft-
hydroxylases which hydroxylate HIF-1α in normoxic conditions, lead- ment and reconstitution. In one study, transfecting the E4ORF gene,
ing to its degradation.77,78 A truncated form of Groβ, a CXC chemo- which activates the Akt-PI3K-mTOR pathway in human marrow endo-
kine which binds CXCR2, mobilizes HSPCs, and a truncated Gro-β, thelial cells, and then transplanting them along with HSPCs into non-
SB-251353, can mobilize primitive hematopoietic cells with enhanced human primates enhanced expansion and long-term reconstitution.81
79,80
engraftment and repopulation activity. Multiple adhesion, chemo- Wharton's jelly MSCs have also been used to expand human umbilical
kine, and matrix molecules are therefore involved in HSPC mobiliza- cord blood HSPCs. CD34+CD38− cells were more expanded in the
tion, and these work through inhibition of the homing and lodgment adherent cell fraction than in the floating cells,82 but how this influ-
mechanisms previously discussed. ences homing is not well studied.

5.1 | Methods to enhance homing 5.1.2 | Modulation of CXCR4/CXCL12

Because stem cell transplantation relies on homing of adequate stem Lipid rafts are specialized areas of the membrane involved in signal
cell numbers to reconstitute marrow function, in cases of inadequate transduction. CXCR4 is incorporated into lipid rafts. Enhanced lipid
autologous stem cell mobilization or in the case of single cord blood raft formation and therefore improved homing through CXCR4 via
transplants with low stem cell availability, methods to enhance stem activation of Rho and Rac is one means to increase homing.83 Mild
cell homing are needed (Table 1). Direct injection of stem cells into heat treatment has been proposed as a means to accomplish this.84
marrow has been attempted to bypass the low efficiency of engraft- Such treatment increased HSPC response to CXCL12 gradients and
ment after intravenous injection, but these approaches have not yet increased HSPC homing in an NSG mouse model.84 Prostaglandin E2
99,100
had broad application in clinical transplantation. (PGE2) increases CXCR4 expression and engraftment of HSPCs.85 In a
phase 1 clinical trial, ex vivo exposure of a single umbilical cord blood
unit to 16,16-dimethyl prostaglandin E2 before reduced-intensity,
5.1.1 | Stromal cell coculture double cord transplantation was found to be safe, and long-term
engraftment of the treated vs untreated unit occurred in 10/12
In vitro, the combination of mild hypoxia (5% oxygen) with MSC treated participants.104 Treatment with histone deacetylase (HDAC)
coculture has been found to enhance the homing capacity of HSPCs inhibitors can lead to increased chemotaxis to CXCL12, thus
STEM CELL HOMING 1247

enhancing homing in NSG mice.105 This was found to be specific to to an increase in systemic EPO.91 Accordingly, the recipient condi-
HDAC5 inhibition. An HDAC inhibitor, valproic acid, may also increase tions at time of HCT are in opposition to the physiologic conditions
86
CXCR4 expression and promote homing. Inhibition of CD26, a pro- which favor HSPC marrow homing at birth. To reverse this unfavor-
tease which degrades other growth factors as well as CXCL12, may able condition, investigators have utilized hyperbaric oxygen (HBO)
also improve homing and engraftment87,88 (see below). therapy to reduce EPO prior to HSPC infusion to lower EPO and thus
Activation of the glucocorticoid receptor bound to a glucocorti- facilitate marrow homing.110 In vivo studies showed improvement in
coid response element in the CXCR4 promoter results in subsequent early UCB CD34+ cell homing110 and in UCB CD34+ cell engraft-
recruitment of the SRC1/p300 histone acetyltransferase complex ment110 in HBO-treated mice. This approach has been investigated in
which promotes histone H4 acetylation of CXCR4 to increase tran- two pilot clinical trials. In a phase I study, HBO exposure before cord
scription. Short-term treatment of cord blood stem cells with gluco- blood graft infusion resulted in erythropoietin reduction and favorable
89
corticoids enhanced homing of HSPCs in NSG mice. Peroxisome engraftment kinetics as compared with historical controls.90 In an
proliferator-activated receptor gamma (PPARΥ) also expanded HSPCs autologous peripheral blood transplant setting where HBO exposure

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by enhancing glucose metabolism,106 but specific homing effects were before stem cell infusion was utilized, neutrophil engraftment time
not described. HIF-1α is a regulator of cell response to hypoxia, and was reduced by 1 day on average and platelet recovery by 2 days.92
the marrow microenvironment is relatively hypoxic. Stabilization of
HIF-1α can enhance mobilization when combined with G-CSF and
plerixafor.77 When myeloid progenitors expand in response to G-CSF, 5.1.5 | CD26 modulation
the marrow environment becomes hypoxic which then leads to stabili-
zation of HIF-1α and increased transcription of VEGF-A which Decreasing CD26/dipeptidyl peptidase IV can enhance chemotaxis to
increases vascular permeability and mobilization. This stabilization can CXCL12. CD26 is a membrane-bound extracellular peptidase
be accomplished by dimethyl prostaglandin E2 with eventual expressed on numerous cell types, including CD45 positive cells. It
upregulation of CXCR4.96 cleaves dipeptides from the N-terminus of polypeptide chains after an
N-terminal X-Pro or X-Ala motif. CD26 cleaves CXCL12 into a trun-
cated analog and therefore inactivates it. Inhibition of CD26 activity
5.1.3 | Fucosylation in CD34+cord blood HSPCs can enhance their migratory response to
CXCL12. CD26 also cleaves other growth factors, so it may also
The binding affinity of some glycoproteins, including selectin ligands, enhance expression of other cytokines which could be important in
can be enhanced when they are fucosylated.107,108 Treatment of cord engraftment as well.88,93 Diprotin A is an inhibitor of CD26, and
blood derived HSPCs with fucosyltransferase can improve rolling and sitagliptin, an approved DPP4 inhibitor which is US FDA approved for
engraftment in murine models. PSGL-1 is expressed in a non- type II diabetes, have been examined as means to enhance cord blood
fucosylated form on cord blood derived HSCs, so fucosyltransferase stem cell engraftment in patients.94 Administration of higher doses of
107
treatment of these cells can enhance homing. Also, ex vivo incuba- sitagliptin resulted in more rapid engraftment in an early phase trial.94
tion of CD144+ cells with fucosyltransferase VI and GDP-fucose on a
fibronectin-collagen–selectin coated nanoscaffold has been accom-
plished with increased expression of CXCR4, VLA4, VLA5, LFA-1, and 6 | MSC HOMING
E-cadherin noted.108
MSCs are defined by adherence to plastic and their capacity to differ-
entiate into various connective tissue lineages. They have angiogenic,
5.1.4 | The role of erythropoietin signaling in proliferative, and immune suppressive capacity as well.95 MSCs are
HSPC homing and engraftment thought to have potential for improving clinical outcomes for inflam-
matory and degenerative diseases. They can be administered intrave-
At birth, HSPCs circulate at high levels, but they rapidly disappear nously or in situ, or they may be mobilized and recruited to injury
109
from blood and home to marrow within hours. This occurs in paral- sites. Each of these modes of delivery requires MSC homing. Less is
lel to a decline in erythropoietin (EPO) levels and this observation indi- known about MSC homing than about leukocyte and HSPC homing.
rectly linked bone marrow homing of HSPCs to EPO levels, and Means to track the fate of MSCs in vivo are needed as is an under-
additional in vitro studies linked EPO/EPO receptors (EPOR) signaling standing of the chemoattractants which guide them to sites of
to HSPC transmigration. For example, in vitro studies showed that injury.95 It is in fact controversial whether MSCs localize to tissue due
UCB CD34+ cells have EPOR and that treating UCB CD34+ cells with to passive entrapment in small vessels or if there are active mecha-
EPO impairs their in vitro transmigration. In contrast, depleting EPOR nisms to guide them to specific tissues.95 Nonetheless, there is much
or treating UCB CD34+ cells with EPO or EPOR neutralizing anti- evidence that MSC homing uses many of the same steps as HSPC
bodies in the presence of EPO restored their transmigration poten- homing. Homing of MSCs is thought to be very inefficient, and like
tial.90 In the setting of hematopoietic cell transplantation (HCT), HSPC homing involves tethering by selectins, activation by cytokines,
chemotherapy and/or radiation induces bone marrow ablation leading arrest by integrins, diapedesis using matrix remodelers, and
1248 LIESVELD ET AL.

extravascular migration toward chemokine gradients.97 MSCs express some studies have shown that MSCs also express CXCR7, the other
CD44 which initiates rolling. Which selectin MSCs use is not well receptor for CXCL12.119
understood as they do not express PSGL-1. Galectin-1 or CD24 may MSCs also variably express multiple other chemokine receptors,
serve as ligands for P-selectin on MSCs.98,111 The activation step is and this expression profile is likely of importance in determining to
mediated by chemokines such as CXCL12 or monocyte chemo- which tissues MSCs will migrate. For example, transforming growth
attractant protein-1 (MCP-1), and this serves to increase the affinity factor-β (TGF-β)-3 is able to increase migration of endogenous mar-
of the integrins which then cause cell arrest. Integrin arrest is probably row MSCs to the femoral head with resultant increase in bone volume
mediated mostly by CD49d (α4β1) which binds to VCAM-1 (CD106) and mineral density in a femur defect model. Indirectly in this model,
on endothelial cells.112 Overexpression of CD49d on MSCs can TGF-β can increase macrophage chemotactic protein (MCP)-1 expres-
increase homing to marrow, and MSCs themselves can express VCAM sion and recruit vascular CD31+ cells as well.120 Tumor necrosis fac-
113
and ICAM. In order to traverse the endothelial basement mem- tor-α can increase MSC migration by upregulating CCR2, CCR3, and
brane, MSCs secrete matrix metalloproteinases (MMPs). Which CCR4.121

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MMPs are involved is not entirely understood, but MMP-1 has been As with HSPCs, fucosylation status of adhesion molecules can
found to have a role in tissue invasion by MSCs.114 Matrix compo- influence homing. Extracorporeal fucosylation of CD44 on rabbit mar-
nents such as tropoelastin have also been found to increase homing row MSCs has been found to increase their homing ability through
and proliferation of MSCs in development and in wound repair.115 CXCL12 and S1P regulation.122 Specific signaling pathways are also
Last, as in HSPC homing, the MSCs must migrate to the site of injury involved in MSC homing and migration as preconditioning of umbilical
guided by chemotactic signals such as PDGFα,116 insulin growth fac- cord-derived MSCs by rapamycin increased cell migration and amelio-
117
tor-1, CXCL12, and other chemokines. Hepatocyte growth factor rated liver ischemia/reperfusion injury in mice via the CXCR4/
and epidermal growth factor have also been shown to be involved in CXCL12 axis.123 Human marrow derived MSCs have been found to
118
MSC chemotaxis and homing. CXCR4 is expressed by MSCs, and transmigrate endothelial lining cells in vitro via activation of the PI3K-
Akt, MAPK, and Jak/Stat signaling pathways in response to CXCL12
stimulated endothelial cell production of PDGF. This leads to activa-
tion of focal adhesion kinase and cytoskeletal changes which can facil-
TABLE 2 Examples of methods to enhance mesenchymal stromal
cell homing itate transmigration.124
Homing and lodgment of MSCs may be tissue-dependent as mar-
Method Example Reference
row MSCs have been found to home to hypopharyngeal cancers,125
Genetic modification Overexpression of 134,135 but they do not appear to home to primary prostate tumors, for exam-
chemokine (CXCR4) or
ple. Likewise, in chronic kidney disease, there is low level homing and
adhesion receptors
(VLA-4) poor survival of transplanted marrow-derived MSCs.126 In mice, mar-
Direct administration to Intramyocardial injection 136 row-derived CXCR4-overexpressing MSCs homed to the intestine
target tissues and improved colitis in inflammatory bowel disease states.127 Some of
Cell surface modulation Fucosylation of selectin 137,138 this differential ability to home is target tissue-dependent, but intrin-
ligands or CD44 sic MSC alterations can also explain this varied capacity. For example,
In vitro priming of MSCs TNF-α or IL-1β exposure 139,140 melanoma cell adhesion molecule (CD146, MCAM) positive MSCs
Decrease intravascular Sodium nitroprusside 141 have greater transmigration to degenerative intervertebral discs than
trapping in lungs intravenously do their negative counterparts.128 Trials of MSC therapies have
Implantation of Scaffold in rabbit meniscus 142 shown benefit in multiple disease states as diverse as systemic lupus
chemokine or cytokine incorporating fibroblast erythematosis, complex perianal fistulas, graft vs host disease, and
impregnated hydrogel growth factor receptor-2
ischemic cardiomyopathy. Their utilization has been studied in many
scaffolding
other diseases as well, often with negative results.129 In myocardial
Pulsed ultrasound of Ischemic limb injury; 143
injured tissue ultrasound treatment infarction, MSCs can have antifibrotic effects, contribute to angiogen-
increased CD31, VEGF, esis, and could differentiate into cardiomyocyte-like cells. There is no
and IL-10 expression direct evidence that MSCs differentiate into functioning
Nanoparticle release of Electrical burn vascular 144 cardiomyocytes, however. Overcoming of the poor viability of
Chemokines; eg, injury transplanted marrow MSCs due to inadequate blood supply and the
CXCL12
generation of free radicals in the damaged myocardial tissue is needed
Magnetic guidance of Liver injury 145
to improve the survival and therapeutic potential of MSCs in myocar-
MSCs treated with
magnetic carbon dial infarction states.130 In addition to invasion of inflammatory sites,
nanotubules both transplanted and native MSCs are involved in bioactive
exchanges of proteins and organelles with stressed cells which can
Abbreviations: IL-1, interleukin-1; IL-10, interleukin-10; MSC, mesenchy-
mal stem and stromal cell; TNF, tumor necrosis factor; VEGF, vascular improve recipient cell function.131 MSCs can also modulate cell death
endothelial cell growth factor. of unfit cells in damaged tissues. This may occur through the
STEM CELL HOMING 1249

production of paracrine factors through calcium ion exchange via con- costly and time consuming in vitro cell expansion and infusion proto-
nexin gap junctions, or via transfer of mitochondria and microRNAs cols.147 Many obstacles to adequately track MSC homing both from
132
by extracellular vesicles and tunneling nanotubules. exogenous infusion and from native tissues exist, and these have been
previously reviewed.148 Table 2 summarizes interventions designed to
modify MSC homing.
6.1 | Methods to enhance MSC homing

To improve efficacy of MSC therapies, improved homing to tissues is 7 | CONC LU SION

required. Since MSC homing efficiency is poor (<10%) in various imag-
ing studies such as whole body positron emission tomography (PET) Stem cell homing is a physiologic process which is capitalized upon in
imaging with radiolabeled MSCs, and intravenously injected MSCs clinical transplant settings. The fact that intravenously injected HSPCs
may be trapped in the lung, methods are needed to enhance MSC can find their way home to the marrow is indeed amazing, and while

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homing.133 These techniques, which can generally increase homing by homing has been studied since the 1970s, there is still much to be
two- to threefold, have been previously reviewed in detail97 and are learned about cellular homing processes. This is especially true as
summarized briefly here. related to MSC homing. Further understanding of homing mechanisms
Genetic modifications have used permanent overexpression of hom- and development of methods to enhance this phenomenon may have
ing factors via viral transduction such as overexpression of CXCR4.134 further clinical benefits and may reduce cell numbers required for suc-
Overexpression of VLA-4 has also been attempted in rat models.135 cessful treatments. As means to use HSPCs and MSCs as targets for
Direct administration of MSCs into the target tissue has been used to gene insertion for therapeutic purposes are further developed, under-
increase homing efficiency, but this does not always yield superior out- standing how these transductions might affect the ability of the stem
comes when compared with intravenously administered MSCs, and this cells to home, migrate, and lodge will also be of importance.149,150
may be tissue and inflammatory state-dependent.136 Cell surface modifi-
cations have included modifications of CD44 through exofucosylation, ACKNOWLEDG MENT
allowing MSCs to utilize E- and L-selectin for homing.137 In vitro priming We wish to thank Allyson Porter for aid in graphical design and Susan
has also focused on CD44 and CXCR4. For example, culture in hypoxic Daley for aid in manuscript preparation.
conditions induced HIF-1α, which then increased the expression of
CXCR4 and CX3CR1.138 Treatment with TNF-α may increase chemokine CONFLIC T OF INT ER E ST
receptor expression including CCR3, CCR4, and CCR5.139 Interleukin-1β The authors declared no potential conflicts of interest.
can induce CXCR3-mediated chemotaxis to enhance MSC trans-
endothelial migration.140 This is mediated through p38 MAPK signaling, AUTHOR CONTRIBU TIONS
and CXCL9 ligand secretion was also enhanced, thus promoting trans- J.L.L., N.S., O.S.A.: manuscript writing, assembly of data, final approval
endothelial migration.140 In murine models, trapping of intravenously of manuscript.
administered MSCs in the pulmonary vasculature can be reduced by
intravenous pretreatment with sodium nitroprusside. It has not yet been DATA AVAILABILITY STAT EMEN T
141
shown if this increases homing to injured organs. Many of these hom- Data sharing is not applicable to this article as no new data were cre-
ing modification modalities have not yet entered human clinical trials ated or analyzed in this study.
examining MSC therapy efficacy.
Others have attempted to modulate MSC homing by altering the
OR CID
target tissue through overexpression of chemokines or through che-
Jane L. Liesveld https://orcid.org/0000-0002-3386-8469
mokine-coated scaffold implantation.142 Pulsed ultrasound applied to
the tissue of interest may also increase MSC homing.143 Targeted
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release of CXCL12 by ROS-sensitive nanoparticles can increase mar-
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