Friedenstein was the first person to identify multi-potential stromal precursor cells; he described the isolation, from the bone marrow, of spindle-shaped, clonogenic cells in monolayer cultures, which he defined as colony-forming unit fibroblasts (CFU-Fs). CFU-F-derived stromal cells can rve as feeder layers for the culture of haematopoietic stem cells (HSCs) and they can differentiate into adipocytes, chondrocytes and osteocytes both in vitro and after transfer in vivo 1. Friedenstein’s original obrvation was the basis of further studies showing that bone-marrow-derived stromal cells are the common predecessors of menchy-mal tissues . Recently, veral studies have reported that multipotential stromal precursor cells can also differ-entiate into cells from unrelated germline lineages (in a process known as transdifferentiation )2,3 (BOX 1; FIG. 1). As a result of their suppod capacity for lf-renewal and differentiation, bone-marrow-derived stromal cells were first considered as stem cells by Caplan and named menchymal stem cells (MSCs)4. However, in the bone marrow, stromal cells are a rare and heterogeneous population of cells that contain a mixture of progenitors at different stages of commitment to the mesodermal lineage and only a very small number of multipotential lf-renewing stem cells, which have recently been identified as sub-endothelial cells that express CD146 (also known as MCAM)5. It is now accepted that most bone-marrow-derived progenitor stromal cells can be considered, after in vitro proliferation, to be MSCs 6. In addition to their potential for tissue repair, MSCs have been shown recently to have potent anti-proliferative
and anti-inflammatory effects. In this Review, we dis-cuss the functional features of bone-marrow-derived MSCs, describe their mechanisms of action and elu-cidate how the findings could be translated to the clinical tting.
Definition of menchymal stem cells
MSCs, which can alternatively be defined as multipotent menchymal stromal cells, are a heterogeneous popula-tion of cells that proliferate in vitro as plastic-adherent cells, have fibroblast-like morphology, form colonies in vitro and can differentiate into bone, cartilage and fat cells 6 (FIG. 1). Although stromal cells that apparently fulfill the criteria for an MSC have been isolated from almost every type of connective tissue 7, MSCs have mainly been characterized after isolation from the bone marrow. Therefore, in this Review, we focus on bone-marrow-derived MSCs.
MSCs that are cultured in vitro lack specific and unique markers. There is a general connsus that human MSCs do not express the haematopoietic markers CD45, CD34 and CD14 or the co-stimulatory molecules CD80, CD86 and CD40, whereas they do express variable levels of CD105 (also known as endoglin), CD73 (ecto-5′-nucleotida), CD44, CD90 (THY1), CD71 (transferrin receptor), the ganglioside GD2 and CD271 (low-affinity nerve growth factor receptor), and they are r
ecognized by the monoclonal antibody STRO-1. The variable expression level of the markers that has been obrved probably aris from species differences, tissue source and culture conditions.
*Department of Neurosciences,
Ophthalmology and Genetics, University of Genoa, Italy. ‡
Centre of Excellence for Biomedical Rearch, University of Genoa, Italy. §
Advanced Biotechnology Center (ABC), Genoa, Italy. ||
IRCSS Giannina Gaslini, Genoa, Italy. ¶
Department of Experimental Medicine (DIMES), University of Genoa, Italy.
Correspondence to A.U. e‑mail:
auccelli@neurologia.unige.it doi:10.1038/nri2395Published online 18 August 2008
Stromal cells
Cells of non-lymphoid origin that form the framework of each organ. By expressing various molecules, the cells can support the adhesion, proliferation and survival of distinct cell subts.
Menchymal stem cells in health and dia
Antonio Uccelli*‡§, Lorenzo Moretta ||‡¶ and Vito Pistoia ||
Abstract | Menchymal stem cells (MSCs) are a heterogeneous subt of stromal stem cells that can be isolated from many adult tissues. They can differentiate into cells of the mesodermal lineage, such as adipocytes, osteocytes and chondrocytes, as well as cells of other embryonic lineages. MSCs can interact with cells of both the innate and adaptive immune systems, leading to the modulation of veral effector functions. After in vivo administration, MSCs induce peripheral tolerance and migrate to injured tissues, where they can inhibit the relea of pro-inflammatory cytokines and promote the survival of damaged cells. This Review discuss the targets and mechanisms of MSC-mediated immunomodulation and the possible translation of MSCs to new therapeutic approaches.
Menchymal tissues The are embryonic tissues of mesodermal origin, consisting of looly packed, unspecialized cells t in a gelatinous ground substance, from which connective tissue, bon
e, cartilage and the circulatory and lymphatic systems develop. T ransdifferentiation
The ability of a non-stem cell to transform into a different type of cell lineage, or when an already partially differentiated stem cell transforms into a different cell lineage or type. Stem cells
A subt of cells that has a lf-renewing capacity and
under appropriate conditions can give ri to veral mature cell lineages.
Mesodermal lineage
In animals with three tissue layers, the mesoderm is the middle layer of tissue, between the ectoderm and the endoderm. In vertebrates, the mesoderm forms the skeleton, muscles, heart, spleen and many other internal organs.The role of MSCs in physiology
Formation of HSC niches in the bone marrow. After
transplantation into the bone marrow of non-obe
diabetic–vere combined immunodeficiency (NOD–
SCID) mice, MSCs have been shown to differentiate into
pericytes, myofibroblasts, bone-marrow stromal cells,
osteocytes, osteoblasts and endothelial cells, all of which
constitute the functional components of the HSC niche that
support haematopoiesis8. The developing haematopoietic
cells are retained in a quiescent state in the bone marrow
until, after the appropriate stimulation, they differentiate
and are then relead in the sinusoidal vascular system.
In the bone marrow, the niche stromal cells surround
the HSCs and their progeny9(FIG. 2). Two types of niche
have been described in rodents. The ‘endosteal niche’ is
formed by osteoblasts that line the endosteal surface of
the trabecular bone, and the ‘vascular niche’ is compod
of endothelial cells and CD146+ sub-endothelial stromal
cells that lie at the abluminal side of bone-marrow
sinusoids5. Stromal cells in both types of niche provide
a sheltering microenvironment that supports the main-
tenance and lf-renewal of HSCs by shielding them
from differentiation and apoptotic stimuli that would
otherwi challenge stem-cell rerves. Moreover, the
niche also controls the proliferation and differentiation of
HSCs and the relea of mature progeny into the vascular
system. The regulation of HSC quiescence, through the
maintenance of HSCs in the G0 pha of the cell cycle in
the endosteal niche, and the control of HSC proliferation,
differentiation and recruitment in the vascular niche can
be ascribed to bone-marrow stromal cells10,11(FIG. 2).
Anti-proliferative activity. Stromal-cell progenitors can
prerve the HSC pool in the bone marrow by maintain-
ing HSCs in a quiescent state; in addition, terminally
differentiated stromal cells such as fibroblasts and chon-
drocytes em to share anti-proliferative effects with
their predecessors, as shown by their ability to inhibit
T-cell proliferation12,13. Fibroblast-mediated modulation
of T-cell respons is triggered by interferon-γ (IFNγ)14,
which indicates that stromal cells in connective tissues
might be involved in the homeostasis of peripheral leuko-
cyte populations15. The results support the hypothesis
that stromal cells, at all stages of maturation, have anti-
proliferative features that are in common with physiologi-
cal stromal-cell niches, including the HSC niche.
The effects of MSCs on immune cells
The immunomodulatory effect of MSCs has only been
described recently, following the obrvation that
bone-marrow-derived MSCs suppresd T-cell pro-
liferation16,17. The studies redirected the attention of
scientists away from the multipotentiality of MSCs towards
their possible regulatory effects on immune cells, and
they paved the way for the characterization of the broad
immunoregulatory activities of MSCs.
ture Reviews |Immunology
Mesoderm Figure 1 | The multipotentiality of MSCs. This figure shows the ability of menchymal stem cells (MSCs) in the bone-marrow cavity to lf-renew (curved arrow) and to differentiate (straight, solid arrows) towards the mesodermal lineage. The reported ability to transdifferentiate into
cells of other lineages (ectoderm and endoderm) is shown by dashed arrows, as transdifferentiation is controversial in vivo.
HSC niche
The microenvironment inside the trabecular bone cavity, which is compod of a specialized population of cells that has an esntial role in regulating the lf-renewal and differentiation of haematopoietic stem cells (HSCs). Haematopoiesis
The commitment and differentiation process that lead from a haematopoietic stem cell to the production of mature cells of all blood lineages — erythrocytes, myeloid cells (macrophages, mast cells, neutrophils and eosinophils), B and T cells, and natural killer cells. Sinusoids
Blood-filled spaces that lack the anatomy of a capillary. Sinusoids generally contain slow-flowing blood, which facilitates cellular interactions. Such vesls are found in the bone marrow and in the liver.Innate immunity. Myeloid dendritic cells (DCs) have a
fundamental role in antigen prentation to naive T cells
following DC maturation, which can be induced by pro-
inflammatory cytokines and/or pathogen-associated
molecules. During maturation, immature DCs acquire
毛笔行书字帖the expression of co-stimulatory molecules and upregu-
late expression of MHC class I and class II molecules
together with other cell-surface markers (such as CD11c
and CD83). MSCs have been shown to inhibit the
maturation of monocytes, and cord-blood and CD34+
haematopoietic progenitor cells into DCs in vitro18–21
(FIG. 3). Furthermore, mature DCs incubated with
MSCs have decread cell-surface expression of MHC
class II molecules, CD11c, CD83 and co-stimulatory
女娲造人动画片molecules, as well as decread interleukin-12 (Il-12)
production, thereby impairing the antigen-prenting
function of the DCs18,20,22–24. MSCs can also decrea
the pro-inflammatory potential of DCs by inhibiting
their production of tumour-necrosis factor (TNF)22.
Furthermore, plasmacytoid DCs (pDCs), which are
specialized cells for the production of high levels of
type I IFN in respon to microbial stimuli, upregulate
production of the anti-inflammatory cytokine Il-10
after incubation with MSCs22. Therefore, it is tempt-
ing to speculate that the combined effects of MSCs on
DCs and pDCs, as described in vitro, could translate
into potent anti-inflammatory and immunoregulatory
effects in vivo.
Natural killer (NK) cells are important effector cells
of innate immunity and they have a key role in anti v iral
and anti-tumour immune respons owing to their
cytolytic activity and production of pro-inflammatory
cytokines25. The function of NK cells is tightly regu-
lated by cell-surface receptors that transduce either
inhibitory or activating signals. NK-cell-mediated lysis
of target cells requires the expression of ligand(s) by the
target cell that are recognized by activating NK-cell
receptors, together with low-level to abnt expression
of MHC class I molecules by the target cell, which are
recognized by the MHC-class-I-specific inhibitory recep-
tors of NK cells26,27. MSCs can inhibit the cytotoxic activity
of resting NK cells by downregulating expression of
NKp30 and natural-killer group 2, member D (NKG2D),
which are activating receptors that are involved in NK-cell
activation and target-cell killing28(FIG. 3).
Freshly isolated, resting NK cells proliferate and
acquire strong cytotoxic activity after culture with Il-2
or Il-15. However, when resting NK cells are incubated
with the cytokines in the prence of MSCs, NK-cell
proliferation and IFNγ production are almost completely
abrogated28,29. Similar to resting NK cells, pre-activated
NK cells had decread proliferation, IFNγ production
and cytotoxicity after culture with MSCs in vitro22,28–32.
However, when the susceptibility of NK cells to MSC-
mediated inhibition of proliferation was compared, pre-
activated NK cells were found to be more resistant to the
effects of MSCs than were resting NK cells28.
Converly, both autologous and allogeneic MSCs
have been shown to be killed by cytokine-activated, but
not resting, NK cells in vitro28,30,31(FIG. 3). The suscepti-
bility of human MSCs to NK-cell-mediated cytotoxicity
depends on the low level of cell-surface expression of
MHC class I molecules by MSCs and the expression
of veral ligands that are recognized by activating
NK-cell receptors29. Incubation of MSCs with IFNγ
partially protected them from NK-cell-mediated cyto-
好奇的toxicity through the upregulation of expression of MHC
class I molecules by MSCs28.
Together, the findings support the possibility that,
following encounter with MSCs in vivo, activated NK
cells could undergo limited functional inhibition that
does not compromi their ability to kill MSCs. As
IFNγ protects MSCs from NK-cell-mediated lysis28, a
microenvironment rich in IFNγ might favour the inhi-
bition of NK-cell function by MSCs, whereas in the
abnce of IFNγ, the balance would be tilted towards the
elimination of MSCs by activated NK cells. However,
the in vivo relevance of the interactions might be
limited only to cas of MSC transplantation.
Neutrophils are another important cell type of innate
immunity that, in the cour of bacterial infections, are
rapidly mobilized and activated to kill microorganisms.
After binding to bacterial products, neutrophils undergo
a process known as the respiratory burst. MSCs have been
shown to dampen the respiratory burst and to delay the
spontaneous apoptosis of resting and activated neutro-
phils through an Il-6-dependent mechanism33(FIG. 3).
previous studies have established a link between the
downregulation of the respiratory burst and an increa
ture Reviews |Immunology
Figure 2 | Stromal cells in the haematopoietic-stem-cell niche. In the bone marrow of trabecular bones, multipotential stromal progenitor cells at different stages of maturation contribute to the formation of the haematopoietic stem cell (HSC) niche. In the endosteal niche, stromal progenitor cells, together with osteoblasts, contribute to the maintenance of HSCs in a quiescent state (G0 pha of the cell cycle). Around sinusoids, angiopoietin-1 (ANG1)+CXC-chemokine ligand 12 (CXCL12)+CD146+ sub-endothelial stromal cells, perivascular stromal cells and sinusoidal endotheli
al cells also regulate HSC maintenance and control HSC proliferation, differentiation and recruitment to the vascular niche. The endosteal niche also contains lf-renewing (dividing) HSCs and mobilized HSCs that are recruited to the vascular niche following proper activation.
Respiratory burst
A large increa in oxygen consumption and the
generation of reactive oxygen species that accompanies the exposure of neutrophils to microorganisms and/or inflammatory mediators.
Activation-induced cell death
A process by which activated, T -cell-receptor-restimulated T cells undergo cell death after engagement of cell-death receptors, such as CD95 or the tumour-necrosis factor receptor, or after exposure to reactive oxygen species.
in the life span of neutrophils 34. MSC-mediated pres-ervation of resting neutrophils might be important in tho anatomical sites where large numbers of mature and functional neutrophils are stored, such as the bone marrow and lungs 35.
Adaptive immunity. After T-cell receptor (TCR) engagement, T cells proliferate and exert veral effector functions, including cytokine relea and, in the ca of CD8+ T cells, cytotoxicity. The proliferation of T cells stimulated with polyclonal mitogens, allogeneic cells or specific antigen is inhibited by MSCs 16,17,22,36–45 (FIG. 3). This inhibition is not MHC restricted as it can be medi-ated by both autologous and allogeneic MSCs. MSC-mediated inhibition of T-cell proliferation depends on the arrest of T cells in the G0/G1 pha of the cell cycle 41,45. MSCs do not promote T-cell apoptosis, but instead support the survival of T cells that are subjected to overstimulation through the TCR and are committed to undergo CD95–CD95-ligand-dependent activation-induced cell death 45. The MSC-mediated anti-proliferative effect on T cells is associated with the survival of T cells in a state of quiescence that can be partially reverd by Il-2 stimulation 38.
Inhibition of T-cell proliferation by MSCs has been
reported to lead to decread IFN γ production both in vitro 22 and in vivo 38 and to incread Il-4 production by T helper 2 (T H 2) cells, which indicates a shift in T cells from a pro-inflammatory (IFN γ-producing) state to an anti-inflammatory (Il-4-producing) state 22.An important T-cell effector function is the MHC-restricted killing of virus-infected or allogeneic cells, which is mediated mainly by CD8+ cytotoxic T lympho-cytes (CTls). MSCs have been shown to downregulate CTl-mediated cytot
oxicity 46 (FIG. 3). Human MSCs puld with viral peptides or transfected with mRNA from tumour cells were protected from lysis by CTls in vitro . pre-treatment with IFN γ incread the cell-surface
cpu散热器
ture Reviews | Immunology
考核方式
Figure 3 | Possible mechanisms of the interactions between MSCs and cells of the innate and adaptive
immune systems. a | Menchymal stem cells (MSCs) can inhibit the proliferation and cytotoxicity of resting natural
killer (NK) cells and their cytokine production in vitro . The effects are mediated by prostaglandin E 2
(PGE 2), indoleamine 2,3-dioxygena (IDO) and soluble HLA-G5 (sHLA-G5) relead by MSCs. Killing of MSCs by
cytokine-activated NK cells involves the engagement of NKG2D (natural-killer group 2, member D) expresd by NK cells with its ligands ULBP3 (UL16-binding protein 3) or MICA (MHC class I polypeptide-related quence A) expresd by MSCs, and of NK-cell-associated DNAM1 (DNAX accessory molecule 1) with MSC-associated PVR (poliovirus receptor) or nectin-2. b | MSCs inhibit the differentiation of monocytes to immature myeloid dendritic cells (DCs), skew mature DCs to an immature DC state, inhibit tumour-necrosis factor (TNF) production by DCs and increa interleukin-10 (IL-10) production by plasmacytoid DCs (pDCs). MSC-derived PGE 2 is involved in all of the effects. The immature DCs are susceptible to killing by cytokine-activated NK cells. The effect of MSCs on DCs impairs the stimulatory effect of mature DCs on resting NK cells and compromis ant
igen prentation to T cells, which cannot then undergo proliferation and clonal expansion. Finally, MSCs dampen the respiratory burst and delay the
spontaneous apoptosis of neutrophils by constitutively releasing IL-6. c | Direct inhibition of CD4+ T-cell function depends on the relea by MSCs of veral soluble molecules, including PGE 2, IDO, transforming growth factor-β1 (TGF β1), hepatocyte growth factor (HGF), inducible nitric-oxide syntha (iNOS) and haem oxygena-1 (HO1).
Defective CD4+ T-cell activation impairs helper function for B-cell proliferation and antibody production. The inhibition of CD8+ T-cell cytotoxicity and of the differentiation of regulatory T cells mediated directly by MSCs are related to the relea of sHLA-G5 by MSCs. In addition, the upregulation of IL-10 production by pDCs results in the incread generation of regulatory T cells through an indirect mechanism. MSC-driven inhibition of B-cell function ems to depend on soluble factors and cell –cell contact, but little is known about the identity of the molecules involved.
HLA-G
A non-classical MHC class Ib molecule that is involved in the establishment of immune tolerance at the maternal–fetal interface, the major soluble isoforms of which are HLA-G1 and HLA-G5.
Notch signalling
A signalling system comprising highly conrved transmembrane receptors that regulate cell-fate choice in the development of many cell lineages, and so are crucial for the regulation of embryonic differentiation and development.
Antibody-creting cells
A term that denotes both proliferating plasmablasts and non-proliferating plasma cells. The term is ud when both cell types might be prent. Multiple sclerosis
A chronic inflammatory and demyelinating dia of the central nervous system. Multiple sclerosis involves an autoimmune respon against components of myelin, which is thought to contribute to pression of MHC class I molecules by MSCs but was
ineffective at restoring CTl-mediated killing47,48, which
indicates that although MSCs inhibit CTl activity they
are not CTl targets.
Regulatory T cells are a specialized subpopula-
tion of T cells that suppress activation of the immune
system and thereby help to maintain homeostasis and
tolerance to lf antigens. MSCs have been reported
to induce the production of Il-10 by pDCs, which, in
turn, triggered the generation of regulatory T cells22,24.
In addition, after co-culture with antigen-specific T cells,
MSCs can directly induce the proliferation of regulatory
T cells through relea of the immunomodulatory HLA-G
isoform HlA-G5 (ReF. 32)(FIG. 3).
Taken together, the findings indicate that MSCs
can modulate the intensity of an immune respon
by inhibiting antigen-specific T-cell proliferation
and cytotoxicity and promoting the generation of
regulatory T cells. In principle, from a clinical per-
spective, excessive inhibition of T-cell respons by
MSCs would render the host vulnerable to infectious
agents. However, fail-safe mechanisms might exist; for
example, MSCs express functional Toll-like receptors
(TlRs) that, after inter a ction with pathogen-associated
ligands, induce the proliferation, differentiation and
migration of MSCs and their cretion of chemokines
and cytokines49–51, and it has been shown that MSCs
lo the ability to inhibit T-cell proliferation due to
impaired Notch signalling after triggering of TlR3 and
TlR4(ReF. 52). Therefore, it is possible that pathogen-
associated molecules might rever the suppressive
effects of MSCs on T cells, thereby restoring efficient
T-cell respons to pathogens52, but it is also possible
that tissue stromal cells can instruct local immune
respons after pathogen infections53.
The cond main cell type involved in adaptive
immune respons is b cells, which are specialized for
antibody production. Studies of the interactions between
MSCs and b cells have produced different results, possi-
bly as a result of the experimental conditions ud41,54–57.
Most published works to date indicate that MSCs inhibit
b-cell proliferation in vitro41,54,56(FIG. 3). MSCs can also
inhibit b-cell differentiation and the constitutive expres-
sion of chemokine receptors56. The effects em to
depend on the relea of soluble factors56 and on cell–cell
contact, possibly mediated by interactions between pro-
grammed cell death 1 (pD1) and its ligands54. However,
other in vitro studies have shown that MSCs could明朝的名人
support the survival, proliferation and differentiation
to antibody-creting cells of b cells from normal individ-
uals57,58 and from paediatric patients with systemic lupus
erythematosus57. Regardless of the controversial in vitro
effects, it should be emphasized that b-cell respons are
mainly T-cell dependent and therefore the final outcome
of the interaction between MSCs and b cells in vivo
might be significantly influenced by the MSC-mediated
inhibition of T-cell functions. Such an assumption is
supported by the results of a study of experimental auto-
immune encephalomyelitis (eAe) in mice injected with
a proteolipid protein (plp) peptide, which is a model
of multiple sclerosis. In this model, the production of
antigen-specific antibodies in vivo was inhibited by
the infusion of MSCs, in addition to a significant
down r egulation of plp-specific T-cell respons, which
indicates that the two events were cloly linked59.
paradoxically, despite their broad immunosuppressive
activities, it is possible that MSCs could function as
non-professional antigen-prenting cells (ApCs). low
concentrations of IFNγ upregulate the expression of MHC
class II molecules by MSCs, which indicates that they could
act as ApCs early in an immune respon when the levels
of IFNγ are low60,61. However, this upregulation of MHC
expression by MSCs, together with the ApC function, was
progressively lost as IFNγ concentrations incread. Such
a mechanism could allow MSCs to function as conditional
ApCs in the early pha of an immune respon and later
switch their function to immunosuppression60.
Most of the immunomodulatory activities of MSCs
described here have been documented by in vitro experi-
ments. As MSCs are derived from stromal progenitor
cells that reside in the bone marrow, their potential
鳖甲
role in the control of physiological immune respons
is unknown, despite the fact that the bone marrow
might be a site for the induction of T-cell respons
to blood-borne antigens62. However, it is possible that
MSC-mediated modulation of immune respons could
occur in vivo following the infusion of in vitro-cultured
MSCs after transplantation.
If this hypothesis is correct, then infud MSCs
could interfere with the interactions between DCs and
NK cells. Mature DCs stimulate the proliferation and
cyto t ocixity of NK cells and their cytokine production,
whereas immature DCs are killed by NK cells25. The dual
immuno s uppressive effects of MSCs on DCs and resting
NK cells could result in the accumulation of immature
DCs in vivo that are potentially amenable to NK-cell-
mediated elimination, but also in the inhibition of NK-cell
proliferation, cytotoxicity and cytokine production
(FIG. 3). However, as discusd earlier, activated NK cells
can kill MSCs. Therefore, the functional outcome in vivo
would be determined by the cytokine microenvironment
关于勤奋的句子in which tripartite NK-cell–DC–MSC inter a ctions take
place. In the abnce of IFNγ, activated NK cells could
kill both immature DCs and MSCs. by contrast, in an
IFNγ-enriched milieu, MSC-mediated inhibition of
immune cells would prevail and target both DCs and
NK cells. Such interactions between MSCs and immune
cells might occur in vivo after MSC transplantation, but
it should also be emphasized that the modulation of DC
differentiation and function by tissue stromal cells could
be viewed as an important mechanism that regulates a
local immune respon53.
As DCs are the main ApCs for T-cell respons,
MSC-mediated suppression of DC maturation would
preclude efficient antigen prentation to and therefore
the clonal expansion of T cells (FIG. 3). Direct interactions
of MSCs with T cells in vivo could lead to the arrest of
T-cell proliferation, inhibition of CTl-mediated cyto-
toxicity and generation of CD4+ regulatory T cells. As
a conquence, impaired CD4+ T-cell activation would
translate into defective T-cell help for b-cell proliferation
and differentiation to antibody-creting cells. The
