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Mediterranean Journal of Hematology and Infectious Diseases
Review Article
Bone Marrow Homing and Engraftment Defects of Human Hematopoietic Stem and
Progenitor Cells
Giovanni Caocci, Marianna Greco and Giorgio La Nasa
Hematology Unit, Bone Marrow Transplant Center, R. Binaghi Hospital, Department of Medical Sciences and Public Health,
University of Cagliari, Cagliari, Italy.
Competing interests: The authors have declared that no competing interests exist.
Abstract. Homing of hematopoietic stem cells (HSC) to their microenvironment niches in the
bone marrow is a complex process with a critical role in repopulation of the bone marrow after
transplantation. This active process allows for migration of HSC from peripheral blood and
their successful anchoring in bone marrow before proliferation. The process of engraftment
starts with the onset of proliferation and must, therefore, be functionally dissociated from the
former process. In this overview, we analyze the characteristics of stem cells (SCs) with
particular emphasis on their plasticity and ability to find their way home to the bone marrow.
We also address the problem of graft failure which remains a significant contributor to
morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT).
Within this context, we discuss non-malignant and malignant hematological disorders treated
with reduced-intensity conditioning regimens or grafts from human leukocyte antigen (HLA)-
mismatched donors.
Keywords: Stem cells; Homing; Engraftment.
Citation: Caocci G., Greco M., La Nasa G. Bone marrow homing and engraftment defects of human hematopoietic stem and progenitor
cells. Mediterr J Hematol Infect Dis 2017, 9(1): e2017032, DOI: http://dx.doi.org/10.4084/MJHID.2017.032
Published: April 19, 2017 Received: January 14, 2017 Accepted: March 18, 2017
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Correspondence to: Giovanni Caocci. Centro Trapianti Midollo Osseo, Ematologia, Dipartimento di Scienze Mediche.
Ospedale “R. Binaghi”. Via Is Guadazzonis, 3, 09126 Cagliari, Italy. Tel. ++390-70-6092800, Fax. ++390-70-6092936. E-
mail: giovanni.caocci@unica.it
Introduction. Allogeneic hematopoietic stem cell
transplantation (HSCT) currently represents one of
the best standard treatment options for a variety of
malignant and non-malignant hematological
diseases. This approach is based on the ability of
donor hematopoietic stem cells (HSC) to localize
to recipient bone marrow (BM) niches. Notably,
only a small percentage of infused HSCs (10%)
engraft within the marrow microenvironment. This
process, known as “Homing,” is not fully
elucidated and our ability to modulate it remains
incomplete. Engraftment failure is a rare but
serious complication of HSCT. In order to gather
the most robust evidence in this area, we
performed a search of the literature available in
Pubmed from January 2005 to January 2017 on
"Hemopoietic stem cell homing and engraftment,"
"Hemopoietic stem cell homing and engraftment
defects" and "Hemopoietic stem cell homing and
chimerism." The present review covers the most
important aspects of recent insights into the
mechanisms of engraftment and defective
engrafting activity of HSCs.
Biological Properties of Stem Cells. Stem cells
(SCs) are ancestral precursors common to all cell
types. They are responsible for the generation of
the tissues that form organs during embryogenesis
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and from there on maintaining the capacity of self-
renewal for the entire life of the organism. The
concept of stem cells dates back to the early 1960s
when Till and McCulloch analyzed bone marrow
to find out which components were responsible for
in vivo blood regeneration.1 Ten days after
transplantation of syngeneic bone marrow (BM)
cells in a murine model, they observed the growth
of nodules in the animal spleens. These nodules,
defined by the authors as “spleen colonies,”
appeared in proportion to the number of injected
BM cells and were therefore thought to derive
from a single BM cell.2 These preliminary
observations made it possible to establish two
main hallmarks of HSCs, namely, their ability to
renew themselves (long-term self-renewal) and to
give rise to mature cell types with characteristic
morphology and specialized functions. Before
reaching a fully differentiated adult status, SCs
generate intermediate cell types called precursors
or progenitor cells. These cells are partially
differentiated and committed to going through
numerous cycles of cell division (committed
precursors) to complete their developmental
pathway in adult tissues.3 Experiments carried out
on the Drosophila fruitfly suggest two different
mechanisms by which SCs can simultaneously
generate identical copies of themselves as well as
more differentiated progeny.4 These two modes of
cell division are referred to as asymmetric cell
division and symmetric cell division. The first
mode is characterized by an intrinsically
asymmetric mechanism whereby only one of the
two daughter cells inherit the regulating factors
necessary for self-renewal and homeostatic control
of the stem cell pool. Hence each single SC
produces a copy of itself plus a differentiated cell
(differentiative division).5-7
In the second symmetric mode, homeostatic
control is maintained at the population level rather
than at single cell level. Two types of symmetric
division have been distinguished: a proliferative
division which results in the generation of two
new stem cells and a differentiation division which
generates two differentiated cells.8 Several
mathematical algorithms have been developed and
are currently available for the simulation of stem
cell proliferation kinetics.9
SCs are classified as embryonic stem cells
(ESCs), embryonic germ cells (EGCs) or adult
stem cells (ACSs), depending on their origin and
different properties. The cells that can virtually
produce any kind of tissue in the body, including
extra-embryonic and placental tissues, are known
as totipotent cells. These totipotent zygote cells
appear about 5-7 days after fertilization when the
fertilized egg starts to divide and produces more
totipotent stem cells. After about 4 days of cell
division, these cells begin to specialize into
pluripotent cells that can generate all embryonic
tissues but not an entire organism. That is why
totipotent stem cells are considered the most
versatile among the different types of SCs.
ESCs and induced pluripotent stem cells
(iPSCs) pertain to the category of pluripotent stem
cells. When pluripotent stem cells differentiate
further, multipotent cells are formed, these cells
are less plastic and more specialized and can
develop into more than one cell type but never all
types of cells of an organism or tissue. Examples
of multipotent cells are HSCs and mesenchymal
stem cells (MSCs). Oligopotent stem cells are
further specialized and are destined to become
specific types of cells. There are two kinds of
hematopoietic oligolineage-restricted cells:
common lymphocyte progenitors (CLPs) which
are programmed to become either T or B
lymphocytes or natural killer (NK) cells and
common myeloid progenitors (CMPs) which are
progenitors for myelo-erythroid lineages. CMPs
give rise to cells that include myelomonocytic
progenitors (GMPs) and megakaryocytic/erythroid
progenitors (MEPs) (Figure 1). More recently, an
impressive study has proposed a new organization
of the hematopoiesis, suggesting a readjustment in
the blood hierarchy during in utero to adulthood
time points.10 Instead of a three-tiers model, the
authors propose a two-tiers scheme in adult bone
marrow: a top-tier which contains multipotent
cells such as HSCs and multipotent progenitors,
and a bottom-tier composed of committed
unipotent progenitors (Figure 2).10 Although often
somewhat neglected by researchers in the past,
unipotent stem cells are unique in their ability to
differentiate along only one cell lineage. These
cells are found in adult tissues and comparison to
other stem cells have the lowest differentiation
potential.11 The potential difference between ESCs
and ASCs can be summed up as follows: the
former are more versatile whereas the latter are
undifferentiated cells that are present in the
differentiated tissue, capable of replacing cells that
have died or lost function. ASCs have been
identified in many different tissues including
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Figure 1. Hierarchical division of the stem cell in hematopoiesis
Figure 2. Redefined model of hematopoiesis. Instead of a three-tiers model, through mulitipotent, oligopotent and then unilineage
progenitor, the authors proposed in adult bone marrow a two-tiers scheme: a top-tier which contains multipotent cells such as HSCs and
multipotent progenitors, and a bottom-tier composed of committed unipotent progenitors.10
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hematopoietic (blood), epidermal, muscle, neural,
mesenchymal, endothelial and gastrointestinal
tissues.
Most of the tissue-specific ASCs persist for
prolonged periods of time in G0 phase of cell
cycle. This quiescent state of ASCs is also referred
to as homeostasis. Differences in the expression of
particular genes and transcription factors
determine the transaction from the quiescent state
to an active phase of the cell cycle, depending on
the organism’s needs.4 Thanks to the presence of
telomeres, the stem cell pool maintains longevity
and genomic stability and is protected against
damage to DNA. Telomeres are specialized repeat
structures of TTAGGG and nucleoprotein
complexes localized at the ends of human
chromosomes. These repetitive DNA sequences at
both ends of the chromosome protect cells from
progressive DNA shortening and degradation
during each repeated cell division.12,13
The fate of HSCs is also strongly influenced by
the BM microenvironment. This
microenvironment is composed of specialized
microanatomical areas called niches. Numerous
studies have shown that interactions between
HSCs and their non-stem cell neighbors in the
niche are critical to the maintenance of the stem
cell pool in the quiescent state or promoting its
self-renewal and proliferation.14 However, this
complex network of signals that occurs in the
niche is far from being fully elucidated.
Bone Marrow Homing. Regenerative or gene
HSC-based therapy is an interesting emerging
field with a huge potential for the cure of
numerous congenital and acquired diseases. There
has been a rapid surge in clinical trials involving
HSC therapies over the last decade. These trials
continue to demonstrate the importance of stem
cells both in replacing damaged tissue and in
providing extracellular factors capable of
promoting endogenous cellular salvage and
replenishment.15-18
A key feature of treatment with HSC is
represented by their ability, once introduced into
the bloodstream to reach their final destination in a
distant target tissue. This intrinsic property is
known as homing. Homing is a crucial step
toward successful engraftment after HSC
transplantation. It was first described several years
ago as an active process that allows for migration
of HSCs through the blood and vascular
endothelium to different organs and BM niches.
Nevertheless, the full comprehension of this
mechanism with its myriad of complex molecular
events remains a challenge. Homing is a process
that relies on intracellular signaling and interaction
between chemokines, chemokine receptors,
adhesion molecules, and proteases, all of which
promote HSC adhesion to microvessels. E-
endothelial and P-endothelial selectin were found
to be essential to cell movement (cell rolling) on
BM microvessels (Figure 3). The intimate contact
with chemo-attractants promotes the expression of
HSC integrins, and through interactions with
several members of the Ig superfamily leads to the
cell arrest on the endothelial surface. Another
important role in HSC homing has been assigned
to intercellular adhesion molecule-1 (ICAM-1)
and vascular cell adhesion molecule-1 (VCAM-1).
These two molecules have been shown to act as
key factors in cell trafficking between blood and
BM.19,20 Also α4β1 integrin and lectins would seem
to have a primary function in HSC attachment to
marrow stromal cells.19 Several studies have
reported that α4β1/ligand interaction contributes to
cellular tethering and rolling. Additionally, it has
been shown that the homing ability of normal
donor cells decreases after treatment with anti-
α4β1.21-23 Further evidence suggesting the
involvement of α4β1-integrin in the homing
process is given in the points below.
ì) α4β1 is widely expressed in both stem and
progenitor cells, exceeding expression of both
L-selectin and 2-integrin taken together;
ìì) α4β1 is constitutively active in HSC and
progenitor cells;
ììì) α4β1 is usually inactive in committed cells. 24-26
The main ligand of α4β1 in committed cells is
VCAM-1. It can, therefore, be reasonably assumed
that all functions are likely to be accomplished
through their interaction. However, homing
mediated by VCAM-1 may rely on other
pathways.
Another important role in homing has been
assigned to concentration of stromal-cell-derived
factor-1 (SDF-1) ligand which increases in the BM
microenvironment after conditioning regimens for
HSC transplantation (Figure 4).27 SDF-1 is a
chemokine isolated from stromal fibroblasts, and it
is abundantly expressed by osteoblasts, endothelial
cells and a subset of reticular cells in the
osteoblast and vascular niches of the bone
marrow.28 SDF-1 is highly conserved among
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Figure 3. Migration and homing of HSCs into the bone marrow microenvironment. E- endothelial and P- endothelial selectin were found to
be important to cell movement (cell rolling) and promote weak HSC adhesion to bone marrow microvessels. The expression of the
chemokine receptor CXCR4 on the HSC surface promotes cell activation via CXCL12 factor. Following stronger interaction between LFA-
1/ICAM-1 and VLA-4/VCAM-1, HSCs arrest on the endothelial surface and migrate through basal lamina. The migration is also promoted
by VLA-4 and VLA-5 interaction with fibronectin, present in the extracellular matrix.
Figure 4. Schematic representation of HSC homing. HSCs infused into blood are more responsive to stromal cell-derived factor (SDF)-1
gradient between bone marrow and blood compared to other factors that are upregulated after transplantation conditioning regimen (S1P,
ATP).
species and constitutively produced in many
tissues. At the basal homeostatic concentration,
SDF-1 interacts as a ligand with the G-protein
coupled receptor CXCR4, promoting HSC
quiescence and survival. The expression of the
chemokine receptor CXCR4 on the HSC surface
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promotes migration and homing into or from the
BM.29 Mouse embryos knocked out for SDF-1 or
CXCR4 show multiple lethal defects, as well as
the absence of BM homing by HSCs. Activation
of the CXCR4 receptor by SDF-1 is one of the
transductional axes most studied in recent years
because of its fundamental importance in
regulating trafficking of HSCs to and from the
BM. It has also been reported that CXCR4-
depleted human cells are insensitive to
mobilization with agonists or antagonists of the
CXCR4 receptor.30 Secretion of SDF-1 in the bone
marrow oscillates in a circadian manner. This
process, although not fully understood, also
involves the activity of the beta3-adrenergic (AdR)
receptor.31
SDF-1-CXCR4 interaction triggers chemotaxis
via intracellular GTPase proteins (heterotrimeric
G-proteins, typically Gi subunits).32 After
binding to SDF-1, CXCR4 undergoes down-
modulation and ubiquitination of the C-terminus
(C-ter) by E3 ubiquitin ligase, in this way
promoting receptor degradation or its recycling via
the endosomal pathway.33,34
Other potential factors involved in the homing
process are the extracellular nucleotides (eNTPs),
such as adenosine triphosphate (ATP) and uridine
triphosphate (UTP), recently described as having a
fundamental role in the modulation of HSC
migration in the presence of SDF-1. Since
extracellular UTP improves HSC migration
toward SDF-1 gradients, pretreatment with eUTP,
it is likely to increase homing of HSCs to the BM
significantly as has been demonstrated in
immunodeficient mice.35 The aforesaid eNTPs act
through P2 nucleotide receptors (P2Rs);
particularly P2YRs. These seven transmembrane-
spanning receptors, also referred to as G-protein
coupled receptors, activate their signal
transduction pathway via activation of
phospholipase C or activation/inhibition of
adenylate cyclase.36
Although the influence of SDF-1 on HSC
chemotactic responses has been well established,
37,38 its role in the different molecular pathways
underlying the early stages of homing remains a
highly discussed and contentious issue.39,40
Indeed, evidence has been produced of HSC
homing to the BM independent of the SDF-1–
CXCR4 axis. Several observations support this
evidence. In 1999, Qing Ma and colleagues
showed that CXCR4-deficient HSCs could
successfully seed BM and give rise to all blood
lineages in an SDF-1- independent manner.41 A
study of HSC homing in a murine model made
refractory to SDF-1 by incubation and co-injection
with AMD3100 (a CXCR4 receptor antagonist)
showed normal or only slightly reduced BM
cellularity. In yet another study, HSCs in which
CXCR4 had been knocked down using an SDF-1
intrakine strategy were competent to engraft.
Myeloablative conditioning for transplantation
most likely induces a highly proteolytic BM
microenvironment that leads to SDF-1 proteolytic
degradation, thereby harshly sharpening its
chemotactic homing gradient.42-44
Adamiak and colleagues recently confirmed the
involvement of the bioactive phosphosphingolipid
sphingosine-1-phosphate (S1P) as a potent
chemotactic factor for HSCs. They performed
hematopoietic transplantation in mice deficient in
BM-expressed sphingosine kinase 1 (Sphk1−/−),
using HCs from normal control mice as well as
mice in which floxed CXCR4 (CXCR4fl/fl) had
been conditionally deleted. They found that
homing and engraftment in the Sphk1−/− mice
was defective after transplantation of CXCR4−/−
BM cells, indicating that SIP expressed in the BM
microenvironment was involved in the homing
process.
SIP levels in the BM are regulated by a balance
in activity between type 1 SP-1 kinase (Sphk1)
and S1P lyase, which has the role of degrading
S1P.45 Since 2010, it has been observed that S1P is
a potent chemoattractant for HSCs, much stronger
than SDF-1.46
It has also been suggested that HSC homing
could be improved by inhibiting CD26 protein
(DPPIV/dipeptidyl peptidase IV). Peptidase CD26
removes dipeptides from the amino terminus of
proteins, and it is has been demonstrated that
endogenous CD26 expression on donor cells
downregulates homing and engraftment.
Therefore, it can be reasonably assumed that by
deleting or inhibiting CD26, it would be possible
to increase HSC transplantation efficiency.42
Besides the BM microenvironment, other
individual genetic factors can have an impact on
successful engraftment of HSCs. For example,
HSC homing is influenced by several molecules
involved in inflammatory and other signaling
pathways of innate immune response.47,48
Ratajczak and colleagues describe how innate
immunity derived factors are external modulators
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of the SDF-1–CXCR4 axis. Because SDF-1 is
extremely susceptible to degradation by
proteolytic enzymes, its availability in biological
fluids may be somewhat limited. However, the
authors observed that at a minimum near threshold
doses, SDF-1 was still able to exert a robust
chemotactic influence on engraftment. They
showed that chemotactic responsiveness of HSCs
to several different types of homing gradients
could be modulated by ex vivo manipulations,
using a strategy that takes advantage of a
hematopoietic stem and progenitor cell (HSPC) -
priming approach. Homing of HSPCs can be
enhanced by ex vivo cell exposure to C3a
(cleavage fragments of the third protein
component of the complement cascade). A trial
evaluating this procedure is currently ongoing at
the Masonic Cancer Center, University of
Minnesota.49
Another molecule that should be tested in the
clinical setting as a potential priming factor is
cathelicidin LL-37, a physiological factor secreted
by BM stromal cells with a more powerful priming
potential than C3a.50
Despite the many questions that still need to be
answered, all these molecules could support a
rationale for the development of innovative
strategies aimed at improving HSC engraftment.
Hemopoietic Stem Cell Homing and
Engraftment Defects. Graft failure remains an
important complication of allogeneic HSCT
because of the high morbidity and mortality
associated with this event. Two different clinical
forms of defective engraftment have been
distinguished: graft failure (GF) and poor graft
function (PGF), both characterized by a primary or
secondary form.51
Graft failure is defined as absolute neutrophil
count of 0.5 x 109/L and/or platelet count of < 20 x
109/L. Primary graft failure is defined as failure to
achieve absolute neutrophil count (ANC) ≥ 0.5 x
109/L for at least 3 consecutive days or ANC
above 0.5 × 109/L, without donor engraftment
(autologous recovery). In secondary graft failure,
patients fail to sustain an absolute neutrophil count
of ≥ 0.5 x 109/L after attainment of primary donor
engraftment or fail to sustain a platelet count of ≥
20 x 109/L, despite neutrophil engraftment.
Consequently, initial donor engraftment with
neutrophil recovery is followed by loss of the
functioning graft.
Both in primary and secondary graft failure,
chimerism may vary from a full recipient status to
a mixed condition in which donor and recipient
cells coexist. Primary graft failure following
myeloablative conditioning regimens generally
determines deep and irreversible aplasia, often
requiring re-transplantation. In secondary graft
failure, autologous recovery is common,
particularly after HSCT with reduced intensity
conditioning (RIC); however, residual
pancytopenia and bone marrow hypocellularity
may persist.52
From a pathogenetic viewpoint, graft failure is
determined by the alloreactive immune responses
of residual host immune effector cells that survive
the conditioning regimen.51 Although the
underlying mechanisms are not entirely known,53 it
has been shown that residual host T cells with
specific anti-donor or suppressive activity play a
fundamental role, both in HLA matched and
mismatched settings. Also, recipient natural killer
(NK) cells are involved in the pathogenetic
pathways leading to graft failure. Their cytotoxic
activity against donor HSCs has been attributed to
the inability of inhibitory killer immunoglobulin-
like receptors (KIRs) on the NK cell surface to
recognize HLA class I molecules expressed on
donor cells.54 On the contrary, donor regulatory T
cells (Tregs and Tr1) and mesenchymal stem cells
(MSC) seem to facilitate engraftment and cco-
transplantation of these cells with HSCs appears to
have the potential to reduce the risk of graft
failure.55-56 Donor-specific HLA antibodies have
also been found associated with an increased risk
of graft failure, mainly in HLA-mismatched and
haploidentical transplantation.57-58
Overall, the incidence of graft failure has been
reported to be between 3 and 15%, in relation to
the different sources of HSCs and transplant
regimens.51,52,-59-62 Several variables have been
investigated as potential risk factors associated
with primary or secondary graft failure. In a large
retrospective study of 967 patients suffering from
hematological malignant and non-malignant
disorders, the parameters increasing the risk of
graft failure were T-cell depletion, HLA-
mismatched grafts, non-malignant disorders and
reduced-intensity conditioning. Conversely, a total
nucleated cell dose of ≥ 2.5 x 108/kg conferred a
reduced risk. Furthermore, primary or secondary
graft failure was associated with lower survival
rates in malignant than in non-malignant
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disorders.61 Recent data, retrospectively collected
from 4684 consecutive patients who underwent
unrelated donor HSCT from 2006 to 2012, showed
in univariate analysis that only the type and status
of disease at the time of transplantation (complete
remission versus no complete remission) were
significant risk factors for graft failure.62
Over the past years, umbilical cord blood
(UCB) has increasingly been used as a source of
HSCs for allogeneic transplantation. Compared to
marrow or mobilized peripheral blood stem cell
grafts from adult donors, significant delays in
neutrophil and platelet engraftment have been
observed. Equally important limitations of this
stem cell source are poor immune reconstitution
and an increased risk of graft failure, at least partly
due to defects in the homing capacity of these
cells. Poor homing of UCB cells has been
associated with low levels of fucosylation of cell
surface molecules that are responsible for binding
to P- and E-selectins expressed in the BM
microenvironment.60 Other factors linked to graft
failure are low stem cell dose, major AB0
incompatibility, female donor grafts for male
recipients and myeloproliferative disease.51
Poor graft function (PGF) is characterized by
the presence of an initial full donor engraftment.
In the primary form, bone marrow cellularity
remains low, and patients present persistent
cytopenias.51 In the secondary form, a prompt
recovery is followed by a progressive decrease in
blood counts. This defect has an incidence after
HSC transplantation ranging between 5 to 25%.63
Several factors have been reported to be associated
with PGF, but the most relevant condition is
represented by graft versus host disease
(GVHD).64 A chronic inflammatory status, with
overexpression of cytokines such as tumor
necrosis factor alfa (TNF-α) and interferon gamma
(IFN-γ), may lead to a decrease in HSC renewal
and proliferation and thus determine peripheral
cytopenias.65,66
Mixed chimerism (MC) after HSCT is an
immunological condition characterized by the
simultaneous presence of different proportions of
both donor- and host-derived cells. This condition
can be transient and evolve in the direction of graft
failure or complete chimerism (CC), or persist for
an extended period. Polymerase chain reaction
(PCR) based on the amplification of variable
number tandem repeats (VNTRs) or short tandem
repeats (STRs) is currently the most common
technique used to monitor this condition.67 In
malignant hematological disorders, MC anticipates
secondary graft failure and relapse. Therefore,
early detection of this condition is essential to
ensure therapeutic interventions capable of
reinforcing the graft, such as donor lymphocyte
infusion (DLI).68
Achievement of persistent MC in patients
transplanted for a chronic non-malignant disease
like thalassemia or sickle cell disease may lead to
tolerance of donor cells toward host tissues with
no further need for immunosuppressive therapy.
Moreover, residual donor hematopoiesis may be
sufficient to eliminate transfusion dependency.69-71
After transplantation for thalassemia, MC occurs
within the first 100 days with an overall incidence
ranging from 30% to 45%. This condition may be
stable or evolve to CC or rejection (secondary
graft failure). Three levels of MC have been
established in thalassemia with different risk
categories for progression to rejection: 1) grade 1,
residual host cells <10%, rejection rates of 3-12%;
2) grade 2, residual host cells ranging between 10 -
25%, rejection rates of 10-50%; 3) grade 3, > 25%
residual host cells, rejection rates of 50-90%.69
Variables reported to be associated with MC in
thalassemia are conditioning regimens, the dose of
infused HSCs and the severity of patient clinical
conditions before transplantation.70 In recent
years, it has been observed that induction of MC is
an effective way of inducing tolerance and
sustained graft function. Reprogramming of the
immune system of the recipient to deliberately
establish MC has been investigated in the solid
organ transplant setting with the aim of improving
the outcome and overall survival rates.71
Conclusions. Homing is a fascinating mechanism
that allows HSCs to reach the BM
microenvironment, engraft and proliferate. This
property has been exploited both in auto and allo
HSC transplant settings and is currently attracting
considerable attention in the field of gene and
regenerative therapy. Increasing advances in gene
delivery techniques have led to a surge of clinical
trials over the past decade. The possibility of using
HSCs as possible carriers of modified genes using
viral vector delivery approaches is rapidly
evolving. Gene therapy with HSCs has an
enormous potential, and different clinical trials
have resulted in functional cures for several
inherited diseases.72 New insights on how
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transplanted HSCs can reach the BM and which
factors influence the homing process are thus
critical.
Graft failure continues to be a major contributor
to morbidity and mortality after allogeneic HSCT
in patients with malignant and non-malignant
diseases, particularly when treated with reduced-
intensity conditioning regimens or grafts from
HLA-mismatched donors. Such cases require close
surveillance and regular monitoring of chimerism.
On the other hand, deliberate induction of mixed
chimerism by modulating the host immune system
could represent an attractive way to improve graft
survival in the future.
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