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Stem cells, inflammation and allergy Blanchet, Marie-Renee; McNagny, Kelly M Dec 7, 2009

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ralAllergy, Asthma & Clinical ssBioMed CentImmunologyOpen AcceReviewStem cells, inflammation and allergyMarie-Renee Blanchet* and Kelly M McNagnyAddress: The Biomedical Research Centre, 2222 Health Sciences Mall, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, CanadaEmail: Marie-Renee Blanchet* - marierenee@brc.ubc.ca; Kelly M McNagny - kelly@brc.ubc.ca* Corresponding author    AbstractRecently, many studies have suggested a potential role for early hematopoietic progenitor cell andhematopoietic stem cell (HSC) recruitment and differentiation in the development of allergy andinflammation. This is based largely on evidence that stem cells or CD34+ progenitor cells arerecruited to the site of inflammation in allergic diseases, likely through many of the same adhesionand chemokine receptors used for stem cell homing to the bone marrow (PSGL-1, CXCL12,alpha4-beta1 integrin, CD44, etc). Once at the site of inflammation, it has been suggested that stemcells could participate in the perpetuation of inflammation by maturing, locally, into inflammatorycells in response to the growth factors released in situ. Here we provide a brief review of theevidence to suggest that hematopoietic stem and progenitor cells (versus mature hematopoieticlineages) are, indeed, recruited to the site of allergic inflammation. We also discuss the moleculesthat likely play a role in this process, and highlight a number of our novel observations on a specificrole for the stem cell antigen CD34 in this process.IntroductionRecently, many studies have suggested a potential role forearly hematopoietic progenitor cell and hematopoieticstem cell (HSC) recruitment and differentiation in thedevelopment of allergy and inflammation. This is basedlargely on evidence that stem cells or CD34+ progenitorcells are recruited to the site of inflammation in allergicdiseases, likely through many of the same adhesion andchemokine receptors used for stem cell homing to thebone marrow (PSGL-1, CXCL12, α4β1 integrin, CD44,etc). Once at the site of inflammation, it has been sug-gested that stem cells could participate in the perpetuationof inflammation by maturing, locally, into inflammatorycells in response to the growth factors released in situ. Thisopoietic lineages in irradiated hosts, can readily beisolated from the thoracic duct lymph of mice.Many of these studies have relied on the use of the CD34marker to identify HSCs. Antibodies to CD34 have beenextremely useful in stem cell purification for clinical useand in furthering the understanding of stem cell biology.Interestingly, through more in-depth analyses, the knowndistribution of CD34 in vivo has recently expanded toinclude many of the key cell types that participate in aller-gic inflammation including mast cell and dendritic cellprecursors, and eosinophils [1-4]. Careful analysis ofthese cell types derived from CD34-deficient mice has ledto a better understanding of the exact functional role ofPublished: 7 December 2009Allergy, Asthma & Clinical Immunology 2009, 5:13 doi:10.1186/1710-1492-5-13Received: 19 October 2009Accepted: 7 December 2009This article is available from: http://www.aacijournal.com/content/5/1/13© 2009 Blanchet and McNagny; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 7(page number not for citation purposes)is further supported by the recent observation that trans-plantable HSCs, with the ability to reconstitute all hemat-CD34 in both stem cell migration and mucosal inflamma-tory cell homing [4,5]. Here we provide a brief review ofAllergy, Asthma & Clinical Immunology 2009, 5:13 http://www.aacijournal.com/content/5/1/13the evidence to suggest that hematopoietic stem and pro-genitor cells (versus mature hematopoietic lineages) are,indeed, recruited to the site of allergic inflammation. Wealso discuss the molecules that likely play a role in thisprocess, and highlight a number of our novel observa-tions on a specific role for the stem cell antigen CD34 inthis process.Hematopoietic stem cells and precursors respond to inflammatory stimuli both in bone marrow and in peripheral tissuesRecruitment of hematopoietic precursors in the lungThere has been a steadily increasing body of literature tosuggest that inflammatory stimuli can have a potent effecton hematopoietic precursors in the bone marrow as wellas recruitment of these cells to the site of inflammation,particularly in the lung [6]. Indeed, Denburg and col-leagues have shown that eosinophil precursors are ele-vated in the bone marrow during development of upperand lower airway inflammation, and could contribute tothe continuous production of eosinophils in asthma.Using a mouse model of upper (allergic rhinitis) andlower (asthma) airway inflammation, this study showedthat at 24 h post challenge, the number of eosinophil pro-genitors is increased in the bone marrow after either upperairway challenge, lower airway challenge, or upper andlower airway challenges with ovalbumin. This increasecorrelated with a boost in mature eosinophils in the bloodand tissue, with a spike in the production of IL-5 andeotaxin. It was further suggested that this increase in eosi-nophil progenitors could contribute to the well-describedaugmentation in mature eosinophil numbers in bloodand tissue in these models.Inflammation and recruitment of eosinophils progenitorsIn addition to this evidence several additional studies,conducted in both humans and mice, support the hypoth-esis that cytokines and chemokines produced duringinflammation influence recruitment and trafficking ofeosinophil progenitors (see figure 1 for a complete list ofmolecules and receptors in human and mouse hemat-opoietic stem cells). For example, it was shown that inhumans, inhaled IL-5 provokes a decrease in CD34+/CCR3 (eotaxin receptor)+ cells in bone marrow aspiratesand bronchial mucosa, likely due to an increase in recruit-ment of these cells to the airway lumen [7]. Allergen chal-lenge has also been shown to provoke an increase inCD34+/IL5R+ cells in the human airway lumen [8], aswell as an increase in CCR3 expression by CD34+ andCD34+/IL-5+ populations in bone marrow aspirates [9].Finally, this CD34+/CCR3+ progenitor population wasshown to migrate in vitro towards the CCR3 ligand,eotaxin. The idea that cytokines, chemokines or antigensupports the hypothesis that hematopoietic progenitorproduction in bone marrow and peripheral migration canbe influenced by an inflammatory environment at distalsites, and that a constant production of hematopoieticprogenitors promoted by inflammatory mediators couldcontribute to the chronicity of inflammatory diseases.Key hematopoietic stem cell homing receptors are used for inflammatory cell migrationBone marrow homing receptors are also essential in inflammationWith a detailed evaluation of the molecules involved inhematopoietic cell migration and homing to the bonemarrow, it quickly becomes apparent that these samereceptors are essential for the efficient homing of matureeffector cells to the site of inflammation. For example, theα4β1 integrin, VLA-4, is a key adhesive receptor for HSCsin the bone marrow and systemic and administration ofVLA-4 blocking antibodies increases the number ofhematopoietic progenitor cells in circulation[10,11]. Sim-ilarly, the inflammatory homing selectin ligand, PSGL-1and its endothelial cell receptors P- and E-selectin, are alsoknown to play a key role in homing and adhesion of HSCsto their bone marrow niche [12]. Interestingly, activationof PSGL-1 by a soluble ligand or an anti-PSGL-1 antibodyleads to suppression of hematopoietic progenitor cell pro-liferation [13]. The hyaluronic acid (HA) receptor, CD44,is also known to play a role in both HSC homing andadhesion to their bone marrow niche [14] and to enhancethe adhesion of inflammatory cells to endothelium at thesites of inflammation [15,16]. Of further interest, CD44ligation is also known to stimulate eosinophil precursorproliferation [17] and could thereby enhance inflamma-tory cell expansion. Finally, we have shown that CD34,itself, is expressed by both HSCs and a number of inflam-matory cell subsets (eosinophils, mast cells, dendritic cellprecursors, etc). Interestingly, on both populations, CD34appears to act as a type of molecular "Teflon" to enhancecell mobility and invasiveness and thereby facilitate traf-ficking of HSCs to the bone marrow and inflammatorycells to inflamed peripheral tissues [2,4,5]. In summary,the same repertoire of functional adhesion, homing andtrafficking receptors are expressed by HSCs and inflamma-tory cells and should endow these cells with a similarpotential for migration.Inflammatory cytokines and chemo attractants are essential for bone marrow traffickingIntriguingly, just as HSCs and inflammatory cells appearto use the same slate of adhesion and homing receptorsfor migration to the bone marrow and sites of inflamma-tion, they also rely on the same chemo attractants, growthfactors and cytokines. For example, CXCR4/CXCL12, ageneral inflammatory chemokine receptor and chemok-Page 2 of 7(page number not for citation purposes)challenge can provoke the production and migration ofeosinophil progenitors is very interesting indeed, since itine ligand, is the only known chemokine receptorexpressed by HSCs and plays an instrumental role in HSCAllergy, Asthma & Clinical Immunology 2009, 5:13 http://www.aacijournal.com/content/5/1/13homing and retention in the bone marrow niche [18,19].Likewise, c-kit, the receptor for stem cell factor (SCF) anda known regulator of stem cell growth and proliferation isalso expressed by peripheral tissue mast cells and regu-lates their chemotaxis, survival, and expansion [20,21].leads to neutrophil precursor activation in the bone mar-row, MMP release, and proteolytic cleavage of c-kit,CXCL12 and CXCR4, etc. Cleavage of these moleculeseffectively deletes the molecular anchors that attract andhold HSCs in the bone marrow and leads to their rapidMouse and human expression of shared molecules between inflammation and stem cellsFig re 1Mouse and human expression of shared molecules between inflammation and stem cells. Comparison of mouse and human expression of 1) bone marrow homing molecules influencing inflammation, 2) inflammatory molecules influencing bone marrow trafficking and 3) inflammatory cytokines produced by hematopoietic stem cells.0286( +80$16%RQHPDUURZKRPLQJPROHFXOHV9/$ [36HOHFWLQ [(6HOHFWLQ [36*/ [ [&' [ [&' [ [,QIODPPDWRU\F\WRNLQHVDQGPROHFXOHV&;&/ [6&) [ [*&6) [+LVWDPLQH [71) [*52EHWD [/36 [&\WRNLQHVSURGXFHGE\+6&V,/ [0&3 [,/ [,/ [*0&6) [Page 3 of 7(page number not for citation purposes)Moreover, G-CSF (a general inflammatory mediator) release into peripheral blood. Further, this blinds HSCs toAllergy, Asthma & Clinical Immunology 2009, 5:13 http://www.aacijournal.com/content/5/1/13signals that could recruit them back to the bone marrowuntil de novo CXCR4 and c-kit membrane receptors can beexpressed on the HSC surface [22,23].Inflammatory mediators and stem cell recruitment to the site of inflammationIn addition to facilitating the potent recruitment ofperipheral blood cells to the site of local inflammation,there is accumulating evidence to suggest that inflamma-tory mediators can influence stem cell recruitment andmigration as well. For example, mast cell precursorsrespond to CXCL12 and migration of the precursors isenhanced by the presence of histamine (signallingthrough the H4 receptors on mast cell precursors) orsupernatants from IgE-stimulated mast cell cultures [24].It has also been suggested that the migration of stem cellsto chemotactic ligands is enhanced by the presence ofTNF-alpha [25]. Another study suggests that the CXCR2ligand GRO-beta mobilizes early stem cells [26]. Theseobservations, combined with the array of inflammatoryhoming receptors expressed on this population suggestthat recruitment of stem cells and hematopoietic progen-itors may occur in allergy and chronic inflammation. Ifthey were to differentiate into mature inflammatory cellsin situ, these cells would be well positioned to influencethe chronicity of disease. Since HSC are known to exit andre-enter the bone marrow through the circulation on aregular basis [27], they could easily be recruited to the siteof inflammation during their normal homeostatic migra-tion.Recently, a study by Massberg et al suggested that HSC are,indeed, recruited from the bone marrow into the circula-tion and travel to the liver, peripheral blood, lung, smallintestine and kidney. These authors also detected HSCs inthoracic duct lymph, which suggests that they havetraveled through the lymph nodes and exited via the effer-ent lymphatics [28]. In this context, it is intriguing to spec-ulate on the ability of HSCs to respond to inflammatorysignals by accelerated differentiation into effector cells insitu. Support for this notion was recently provided by theobservation that HSCs express the innate pathogen pat-tern recognition receptor, TLR4, and in response to LPS (aTLR4 ligand), these cells proliferate vigorously in situ, anddifferentiate into mature hematopoietic lineages (den-dritic cells) [29]. This is the first evidence to suggest thatrecruitment, proliferation and accelerated maturation ofcirculating HSCs in response to an allergen or bacterialinfection could, in fact, have a direct contribution to theinflammatory immune response.In summary, during either steady state trafficking, or inresponse to potent systemic inflammatory signals, HSCscules for trafficking to the sites of inflammation (see fig-ures 2 and 3). Furthermore, evidence is emerging tosuggest that these cells can respond to inflammatory sig-nals with the rapid production of required cell types at thesite of inflammation.Do stem cells, themselves, influence the further recruitment of inflammatory cells?A role for stem cells in chronic inflammationSeveral recent studies have argued that the "stem cells",themselves, could enhance allergy and chronic inflamma-tion via production of inflammatory factors and chemo-tactic mediators, thereby promoting recruitment of eitherother precursors or mature hematopoietic cells. Followingthis line of reasoning, it was shown that human CD34+progenitor cell supernatants attract RAW 264.7 macro-phages cells in vitro [30], suggesting that progenitor cell-produced chemotactic agents are released by hematopoi-etic precursors. Moreover, in a mouse model of angiogen-Inflammatory receptors and mediators shared between stem cells and inflammatory cellsFigure 2Inflammatory receptors and mediators shared between stem cells and inflammatory cells. List of inflammatory receptors and mediators shared between stem cells and inflammatory cells. Modulation of these mediators/receptors was reported to mediate stem cell mobilising, which could allow them to contribute to development of inflammatory and allergic diseases. *: receptors that were 71)*&6)(RWD[LQ&&5&;&5$OSKD %HWD LQWHJULQ/367/5 6&).LW+\DOXURQLF $FLG&'&;&/&;&5( 6HOHFWLQ36HOHFWLQ36*/ F5HFHSWRU 0HGLDWRUOLJDQGUHSRUWHGRQVWHPFHOOVLQOLWHUDWXUH)LEURQHFWLQ9&$071)5*&6)5&;&/Page 4 of 7(page number not for citation purposes)are well equipped with the appropriate cytokine receptors,chemokine receptors and adhesion and homing mole-reported to be expressed in stem cells.Allergy, Asthma & Clinical Immunology 2009, 5:13 http://www.aacijournal.com/content/5/1/13esis, matrigel inserts containing CD34+ progenitor cellswere shown to rapidly recruit monocytes/macrophages aswell as neutrophils in NOD SCID mice in vivo. In this case,it was shown that attraction of monocytes occurredthrough production of IL-8 and MCP-1 by the CD34+ pro-genitor cells [31]. An additonal recent study has con-firmed that CD34+ human progenitor can act as effectorcells in allergy. Indeed, it was shown that they expressreceptors for the epithelial and mast cells cytokinesthymic stromal lymphopoietin (TSLP) and IL-33 [32].CD34+ cells were stimulated with the combination ofTSLP and IL-33, they produced a variety of cytokinesincluding IL-5, IL-13 and GM-CSF. These three mediatorsare well known to recruit and promote chronic inflamma-tion in allergy and asthma. Finally, that study demon-strated that the sputum from allergic/challenged patientscontained IL-5 and IL-13 positive CD34+ blood cells, con-firming that an allergic environment leads to cytokineproduction by hematopoietic precursors. All in all, thissuggests that CD34+ precursors could participate into pro-Proposed models for the role of stem cells in development of inflammationFigure 3Proposed models for the role of stem cells in development of inflammation. A) Production of inflammatory media-tors during inflammation can increase the number of committed progenitor cells. B) Chemotactic mediators released during inflammation can provoke the recruitment of stem cells from the circulation to the site of inflammation where they undergo a rapid proliferation phase, followed by terminal differentiation into inflammatory cells (mast cells, dendritic cells, eosinophils, neutrophils, etc) at the site of the inflammatory reaction, contributing to development and chronicity of disease. C) Inflamma-tory mediators provoke the release of proteases (MMPs) by granulocytes or stem cells within the bone marrow, which cleave the molecular anchors of stem cells and increase their release in the circulation.,QFUHDVHG SURGXFWLRQRIFRPPLWWHG SURJHQLWRUV ZLWKLQ WKHERQH PDUURZDQGUDSLG SUROLIHUDWLRQ ,QVLWXGLIIHUHQWLDWLRQ5HOHDVHRISURWHDVHV&OHDYDJHRIPROHFXODU DQFKRUV$%&5HOHDVHRIVWHPFHOOV LQFLUFXODWLRQ5HFUXLWPHQWRIFLUFXODWLQJVWHPFHOOVYLDLQIODPPDWRU\PHGLDWRUVERQHPDUURZVHHILJXUHPage 5 of 7(page number not for citation purposes)These two cytokines are known to drive towards Th2- IgEdependant allergic reactions. Moreover, when thesemoting chronic inflammation.Allergy, Asthma & Clinical Immunology 2009, 5:13 http://www.aacijournal.com/content/5/1/13CD34+ cells in mice: a pure population of progenitor cells?A caveat to this previous model, however, is that CD34has recently been shown to be expressed on a number ofmouse inflammatory cells and precursors (such as mastcells, eosinophils and dendritic cells). Thus, it is possiblethe inflammatory cytokines detected in this study whereproduced by more mature CD34+ inflammatory cellsrather than CD34+ progenitor cells. Our observation thatCD34+ mast cells and their precursors express the samecohort of cell surface markers and antigens[2] suggest thatgreat care must be exercised in distinguishing stem cellsfrom mast cells. Since mast cells are extremely potent elab-orators of inflammatory mediators and are present inperipheral tissues at the same frequency as circulatingstem cells, this represents a significant problem in theinterpretation of many previous studies.Contribution of stem cells to inflammatory disease: a possible clinical implicationWith the afore mentioned caveat aside, functional assayshave confirmed that bona fide HSCs and hematopoieticprecursors, with the ability to generate multiple hemat-opoietic lineages in lethally irradiated recipients, do circu-late through the peripheral blood and lymph andtherefore are positioned to home to the sites of inflamma-tion. Although it could be argued that the numbers ofthese circulating and recruited progenitors would be toolow to make a major contribution to allergy and inflam-matory disease development, it is important to bear inmind that as HSCs enter the differentiation pathway andbecome "transient amplifying cells", they exhibit a trulyremarkable capacity for proliferation and expansion. Thisexpansion of precursors prior to terminal differentiationand would allow a very limited number of recruited stemcells to have a major impact on local inflammatory cellgeneration. There are no studies to date that have investi-gated whether blockade of their recruitment could influ-ence the course of inflammation. However, a closer lookat the blockade of some molecules implicated in their traf-ficking could help us determine whether this avenuecould be of therapeutic value.ConclusionThe evidence of shared receptor expression and chemotac-tic potential between inflammatory cells and stem cells isconvincing. Moreover, there seems to be a direct effect ofinflammation on stem cell recruitment, potentially redi-recting the homing of HSCs destined for the bone mar-row, to the site of inflammation in diseases like allergy. Asthe understanding of these interactions grows, we shouldhave a better impression of the extent of stem cell recruit-ment to the development of allergic inflammatory dis-eases.Competing interestsThe authors declare that they have no competing interests.Authors' contributionsM-RB and KMM contributed equally to the writing of thismanuscript.AcknowledgementsSupported by CIHR grant #MOP-64278 and the Allergen Network Centre of Excellence. KMM is a Michael Smith Foundation for Health Research sen-ior scholar.References1. Erdag G, Qureshi HS, Patterson JW, Wick MR: CD34-positive den-dritic cells disappear from scars but are increased in pericic-atricial tissue.  J Cutan Pathol 2008, 35(8):752-6.2. 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