BMSCs and Hematopoiesis PDF

Immunology Letters 168 (2015) 129–135 Contents lists available at ScienceDirect Immunology Letters...

Immunology Letters 168 (2015) 129–135 Contents lists available at ScienceDirect Immunology Letters journal homepage: www.elsevier.com/locate/immlet BMSCs and hematopoiesis Andrés García-García a,b , Carlos L.F. de Castillejo a,b , Simón Méndez-Ferrer a,b,∗ a Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain b Stem Cell Institute and Department of Haematology, University of Cambridge, and National Health Service Blood and Transplant, Cambridge Biomedical Campus, CB20PT Cambridge, United Kingdom a r t i c l e i n f o a b s t r a c t Article history: Recent discoveries have significantly expanded our previous knowledge about the role of bone marrow Received 23 June 2015 mesenchymal stem cells (BMSCs) in hematopoiesis. BMSCs and their derivatives modulate blood pro- Accepted 23 June 2015 duction and immunity at different levels but a prominent role has emerged for BMSCs in the regulation Available online 17 July 2015 of hematopoietic stem and progenitor cells (HSPCs). Additionally, BMSC-like cells regulate B and T cell lymphopoiesis and also probably myelopoiesis. Furthermore, BMSCs might also exhibit key regulatory properties in non-physiological conditions. BMSCs in extramedullary sites might provide a permissive microenviroment to allow for transient hematopoiesis. BMSCs might be also involved in the manifesta- tion and/or the development of hematopoietic diseases, as stemming from their emerging roles in the progression of hematological malignancies. Here we review some key molecular pathways, adhesion molecules and ligand/receptor interactions that mediate the crosstalk between BMSCs and hematopoi- etic stem cells (HSCs) in health and disease. The development of novel markers to visualize and isolate individual cells will help to dissect the stromal–hematopoietic interplay. Crown Copyright © 2015 Published by Elsevier B.V. All rights reserved. 1. BMSCs & HSPCs signaling. Simultaneously, Zhang et al. also identified bone- lining osteoblasts as key regulators of bone marrow niche size. BMSCs and HSCs were described as the initiating cells responsi- In this case, the molecular pathway involved was BMP signaling ble for bone marrow reconstitution after mechanical depletion of. Angiopoietin-1 produced by endosteal cells was also found marrow cavity (see Ref. for a review). BMSCs lie at the top of the to promote HSC quiescence by binding to Tie2 receptor in HSCs hierarchy of bone marrow stromal elements giving rise to cartilage,. Angiopoietin-1 has been recently found to be mainly pro- bone and adipose tissue. Since their discovery in the bone marrow duced by leptin receptor+ mesenchymal stromal cells and also by Friedenstein et al. , it has been proposed that BMSCs support by HSPCs, which contribute in this way to regenerate their own hematopoiesis through direct and indirect mechanisms. Dexter niche after irradiation. Osteoblastic cells also regulate prim- et al. devised murine long-term cultures in which bone marrow itive HSCs through thrombopoietin/MPL signaling , although mesenchymal stromal cells could maintain hematopoiesis in vitro the megakaryocytes themselves have been recently proposed by. By preserving HSC properties in the bone marrow, BMSCs are the same group as the main source of thrombopoietin the bone therefore key components of the so-called “stem cell niche”. marrow. However, more primitive mesenchymal cells pro- When the first evidences of the existence of a stem cell gressively acquired a more prominent role in the maintenance and niche in the bone marrow emerged, several studies suggested regulation of HSCs, compared with mature osteoblasts. that osteoblastic cells could have an active role in the regula- In the mouse, BMSCs identified based on the expression of the tion of hematopoiesis given the proximity between HSPCs and intermediate filament protein nestin were found highly enriched the inner bone layer (“endosteum”) of the bone marrow [5–7]. In in fibroblastic colony-forming-unit activity and self-renewal capac- 2003 a turning point took place as Calvi et al. provided for the ity in serial transplantations. Nestin+ BMSCs express high levels of first time in vivo data suggesting that osteoblastic lineage cells HSC maintenance genes, like Cxcl12 and c-kit ligand, and their are regulatory components of the HSC niche via Notch pathway depletion reduced HSC activity and bone marrow homing. Mesenchymal progenitor activity was soon after found also enriched in a bone marrow reticular stromal cell population charac- ∗ Corresponding author at: NHS Blood and Transplant. Cambridge Biomedical terized by high expression of the key HSC maintenance chemokine Campus. Cambridge, CB2 0PT, UK. Cxcl12, therefore named Cxcl12-abundant reticular (CAR) cells E-mail address: [email protected] (S. Méndez-Ferrer). http://dx.doi.org/10.1016/j.imlet.2015.06.020 0165-2478/Crown Copyright © 2015 Published by Elsevier B.V. All rights reserved. 130 A. García-García et al. / Immunology Letters 168 (2015) 129–135 Fig. 1. Interactions between BMSCs identified using different markers and HSPCs. Diagram showing several pathways mediating the interaction of BMSCs identified using markers like osterix (Osx), nestin, Leptin receptor, neural/glial antigen 2(NG2), Cxccl12::GFP knock-in (CAR), derivative of Paired related homeobox 1 (Prx1)+ lateral plate mesoderm. CLP, common lymphoid progenitor; CMP, common myeloid progenitor; MPP, multipotent progenitor; BMPs, bone morphogenetic proteins; OPN, osteopontin; HA, hyaluronic acid. [16,17]. Later, several studies confirmed the importance of Cxcl12 seem to improve engraftment when co-transplanted with HSCs expressing cells in HSPC regulation but suggested different roles [28,29]. Several works showed that ex vivo expanded BMSCs could depending on their source and location. Cxcl12 expression by engraft in recipient marrow after intramedullary transplantation. osteoblastic cells would be important in B-cell lymphoiesis and in These BMSCs could give rise to most stromal component and HPC retention in the bone marrow; however, perivascular Cxcl12 enhance engraftment and HSC function in the recipient marrow expression would be key to directly support HSCs [18,19].. Le Blanc et al. co-transplanted BMSC with HSC and achieved The precise identity of the mesenchymal stromal populations faster engraftment of neutrophils and platelets with 100% donor that contain BMSC and HSC niche functions remains debated. In chimerism. 2012 Ding et al. identified perivascular HSC-supporting stromal Multiple studies have shown that BMSCs contribute to HSC cells using the expression of the HSC maintenance factor stem long-term maintenance, proliferation and differentiation through cell factor (Scf; also known as kitl). This cell population over- different signalling pathways (Fig. 1). As indicated before, lapped only with Nestin–GFPlo cells, and not with Nestin–GFPhi Cxcl12–Cxcr4 axis is a key player in the interaction between BMSCs cells. However, Kunisaki et al. proposed NG2+ Nestin–GFPhi and HSCs, but many other signaling pathways participate in this cells as components of an arteriolar HSC–BMSC niche. Depletion of crosstalk. For instance, Rac GTPases in nestin+ perivascular BMSCs NG2+ cells promoted HSC proliferation and reduced its long-term have been recently involved in HSC regulation [32,33]. Other stud- repopulating capacity in vivo. Finally, Zhou et al. suggested that ies suggest that long-term activation of Gs signaling in osteoblastic leptin receptor positive cells contained all BMSC activity and rep- cells negatively affect HSC maintenance [34,35]. Also, Wnt signal- resented the main source of adult bone formation , although ing regulates the survival, self-renewal and differentiation of HSPCs leptin receptor+/Lepr-cre-traced cells appeared more abundant [36,37]. Agrin, a proteoglycan involved in neuromuscular junction, than previously described and could contain different cell types also participate in the crosstalk between BMSCs and HSCs. with distinct functions. In addition to soluble secreted factors or extracellular proteins, In the human system, CD146+ perivascular BMSCs, reported cummulative evidence suggests that direct cell-to-cell contact is initially by Sacchetti et al. as the in vivo correlate of human CFU- important in HSC regulation by BMSCs. As mentioned before, Notch F-initiating cells , can support long-term persistence of human pathway is one example. Gottschling et al. reported that ␤1- myelolymphoid HSPCs through cell to cell contact and via Notch integrin expression in human BMSCs could promote self-renewing pathway. Other studies also used the CD105 antigen to identify divisions of HSCs. There are discrepancies whether BMSCs murine mesenchymal stem cells. In this sense, non-adherent mes- and/or osteobalstic cells can modulate HSPCs through the adhe- enchymal spheres derived from human CD146+ CD105+ nestin+ sion molecule N-cadherin [40,41]. Other molecules that have been cells could promote human umbilical blood HSC expansion. involved in BMSC–HSC interactions will not be discussed here due Pinho et al. also showed HSC supporting activity using murine or to space constrictions. adult fetal PDGFR␣ + CD51+ nestin+ BMSCs. However, adult human BMSCs are highly enriched in the PDGFR␣-CD271+ cell frac- 2. BMSCs, lymphopoiesis and myelopoiesis tion. There is now broad evidence suggesting that BMSCs have posi- As part of the study of the bone marrow stem cell niches, many tive effects in HSC transplantation. Both human and murine BMSCs efforts have been directed towards understanding the interactions  A. García-García et al. / Immunology Letters 168 (2015) 129–135 131 originate a suitable microenvironment for HSPCs. In addition, mesenchymal stromal cells implanted subcutaneously together with endothelial colony-forming cells can establish a functional hematopoietic microenvironment. Human normal and leukemic cells engrafted and remained functional in this extramedullary site. 4. BMSCs in hematological malignancies Research in the past ten years has definitely proved that the microenvironment, and specially BMSCs, play more than a bystander role in hematopoietic diseases. Alterations of stromal cells have been implicated in the pathogenesis of myeloprolif- erative neoplasms (MPNs), including chronic myeloid leukemias (CMLs), and also in acute myeloid leukemias (AMLs). MPNs are hematological malignancies arising from mutations in the HSCs, and present with an overproduction and accumulation of myeloid cells. Several mutations have been described in human patients, Fig. 2. BMSCs and/or their derivatives directly regulate HSPCs and mature blood including mutations in the Janus Kinase 2 gene (the most frequent cells. Molecules involved in the crosstalk between mesenchymal stromal cells, lym- phopoiesis and myelopoiesis. Mesenchymal stromal cells modulate T cell early one being JAK2V617F) [53–56], the thrombopoietin receptor MPL lymphopoiesis by cell-to-cell contact through CD49d and CD90. They also stimu- , and calreticulin [58,59]. Furthermore, the list of additional sec- late B cell lymphopiesis through VCAM-1, CXC12 and IL-7. However, Activin A and ondary mutations, mostly in epigenetic regulators, has increased as G-CSF inhibit B cell formation, prompting myeloid differentiation. KITL, IL-6 and IL-3 of late. Mutations in ASXL1, CBL, IDH, IKZF1, and TET2 have been directly contribute to myelopoiesis. linked to an increased frequency of leukemic transformation in patients (see Ref. for a review). In the case of leukemias, cytoge- between BMSCs and HSCs. However, cummulative evidence sug- netic abnormalities and chromosomal translocation originate the gests that the BMSC derivatives could modulate hematopoiesis disease and promote the expansion of the leukemic stem cell (LSC) by regulating committed hematopoietic progenitors. An in vitro clone (reviewed in Ref. ). study suggested a role of mesenchymal stroma in early T-cell In 2007, Walkley et al. published two groundbreaking studies lymphopoiesis through adhesion molecules. Another study providing (i) direct verification that niche alterations were required proposed a negative effect of mesenchymal stroma in B-cell for MPN-like disease inception and (ii) validation of the hypothesis lymphopoiesis mediated by activin A. However, Ichii demon- that cells from lineages other than the hematopoietic had leuke- strated that human BMSCs in coculture with human CD34+ cord mogenic potential. Genetic deletion of the retinoblastoma gene blood cells can support B lymphopoiesis. Zhu et al. showed or the retinoic acid receptor gamma (RAR␥) provoked a in vitro that osteoblasts are necessary and sufficient for B-cell com- non-transplantable MPN-like phenotype. More strikingly, in both mitment and maturation. Recently, it has been proposed that models the disease was recapitulated only when cells from disease- granulocyte colony-stimulating factor (G-CSF) could modify BMSCs carrying mice were transplanted into recipients bearing the genetic properties resulting in suppression of B lymphopoiesis in mice. lesions, hence providing categorical confirmation of the necessity As occurs with lymphopoiesis, some studies indicate that BMSCs of an altered niche for disease manifestation. Thereafter, several and/or their derivatives could affect myelopoiesis. Previous evi- reports have surfaced to substantiate the idea that modifications dence suggested the possibility that osteoblasts could stimulate in stromal cells are essential to obtain a transplantable pheno- myelopoiesis by sustained G-CSF release. Later, Angelopoulou type. Specific deletion of Notch pathway component Mind bomb et al. showed that myelopoiesis and megakaryiopoiesis were 1 in stromal cells , deletion of miRNA processing gene Dicer1 improved when CD34+ HSCs and human BMSCs were cotrans- in BMSCs , and the presence of novel mutations in stromal planted in immunodeficient mice. However, it was described cells from human patients different from the HSC driver mutation later that the myelopoietic supporting capacity of BMSCs is inde- in patients altogether suggest a prominent role of BMSCs in pendent of their multipotency and it is more related to their myeloid neoplasias. ostoegenic/adipogenic differentiation and their glycosylation sta- Some questions have arisen in the field: are the lesions of the tus. microenvironment secondary events? To what extent do stromal Interestingly, mature hematopoietic cells can also modulate cells switch from their normal physiology to a malignant one? hematopoietic progenitors through BMSCs. For instance, CD8+ T- Could aberrant BMSCs actually drive and initiate disease? Many cells can activate early multipotent progenitors during acute viral advances have been made using human samples from patients infection to promote temporarily myelopoiesis. suffering from MPNs as well as an ample variety of murine mod- In summary, it seems that BMSCs and/or their derivatives els. Data from both of these sources portray consistent results: (particularly osteoblasts) naturally support B-cell lymphopoiesis; mesenchymal stromal cells display aberrant secretory phenotypes however, inhibiting this capacity could favor myelopoiesis (Fig. 2). [67–69], disrupted signaling pathways [70–72] or atypical gene expression patterns. For instance, in myelodysplastic syn- 3. BMSCs in extramedullary hematopoiesis drome (MDS), BMSCs express anomalous levels of CXCL12 , leukemic inhibitory factor (LIF), VEGF, and N-Cadherin or DICER Hematopoiesis outside the bone marrow is often associated , among others. The altered expression profile of these BMSCs with pathological processes. Some studies indicate that BMSCs has been proposed to be crucial for the remodeling of the neopla- could also favor hematopoiesis in these abnormal situations. sic niche by creating a malignant microenvironment which favors Khaldovanidi et al. reported that interleukin 5 induce spleen col- the development and maintenance of mutated MPN cells. Convinc- onization with mesenchymal progenitor cells, which in turn favor ing data have been presented using xenograft models in which the establishment of hematopoiesis providing necessary signals to CD34+ hematopoietic cells plus mesenchymal stromal cells from 132 A. García-García et al. / Immunology Letters 168 (2015) 129–135 Fig. 3. Some regulatory mechanisms in place within the malignant bone marrow niche. (A) Osteoblastic lineage bias. (B) Disruption of signal transduction pathways in BMSCs. (C) Defective sympathetic innervation on nestin+ cells. (D) Abnormal production or inhibition of healthy HSC maintenance factors. (E) Activation of niche remodeling led by the bone-lining osteoblasts acting on the neoplasic clone. (F) Expansion of the mutated blood cell. (G) Reinforcement of the malignant microenvironment through paracrine loops between the BMSCs and the mutated HSCs. disease-carrying donors were transplanted into immunodeficient mutant HSCs and their healthy counterparts that are transformed NSG mice. Strikingly, mice transplanted with mesenchymal stromal into “leukemic-like” pro-inflammatory cells [82,83]. Nevertheless, cells and CD34+ cells displayed a significantly higher reconstitu- several key studies have situated stromal elements in the midst of tion rate than mice transplanted only with CD34+ cells or together fundamental niche transformations. One example of the stromal with mesenchymal stromal cells from healthy donors. These alterations in myeloid diseases is the loss of bone mass occurring cotransplation setups have aided to illustrate the remodeling prin- in the blast phase of CML or in AML. Although partially explained ciple: mutant cells hijack the normal function of the stromal cells by an increase of osteaclastic bone resorption, the decrease in bony and therefore a modified, disease-prone, and even drug-resistant matrix was the result of an increase in the levels of cytokine CCL3 niche [76–80] is formed. produced by leukemic cells , which effectively decreased the Drawing parallels to the homeostasis situation, mutant HSCs number of both osteoprogenitors and the more mature osteoblasts reside within their particular microenvironment that works to. Similar endocrine signals can regulate both osteoprogenitor maintain the neoplasm and to suit the regulatory pathways cells and HSCs. For instance, work from the Morrison lab and our involved in the expansion and progression of disease. Multiple group has shown recently that the female sex hormones estro- reports have shed light on niche remodeling mechanisms. One is gens, known to be bone anabolic agents, also differentially regulate based on the transcriptional reprogramming of BMSCs to (i) con- HSC self-renewal, proliferation and survival [86,87]. Endogenous fer an advantage to the mutant hematopoietic cell, or (ii) impair estrogens might partially explain the higher incidence and sever- healthy hematopoiesis; or possibly both concomitantly. Neopla- ity of hematological malignancies in men, compared with women, sic cells rely most heavily on signaling cascades prompted by the and selective estrogen receptor modulators might be useful in the paracrine action of secreted factors or cytokines. In CML, mutant treatment of MPN. Linked to the notion of a dysfunctional cells have been reported to induce the upregulation and secretion mesenchyme compartment, alterations in gene expression in mes- of placental growth factor (PIGF) in stromal cells, which in turn enchymal cells have been deemed to have oncogenic potential and stimulates the proliferation of CML cells in a positive loop fashion to increase the likelihood of leukemic transformation in human. In an additive manner, G-CSF secreted by CML cells leads to a patients. Specific deletion of the Schwachman–Bodian–Diamond decrease in BMSC-produced CXCL12, leading to complications with (sbds) gene in cells from mesenchymal origin prompted myelodys- normal HSC maintenance and retention. plastic symptoms in mice. Furthermore, it has been proposed In an attempt to establish unified patterns for the whole spectra that, in MPNs, BMSCs might develop a bias towards generation of myeloid malignancies, one needs to underscore and highlight of malfunctioning osteoblastic progenitors, ultimately leading to the pivotal role of BMSCs and their progeny as major sources of faulty hematopoiesis and creating fertile grounds for marrow fibro- cytokine production. Paracrine loops are known to occur between sis and osteosclerosis. Altogether, available data seem to agree  A. García-García et al. / Immunology Letters 168 (2015) 129–135 133 with the hypothesis that mutated HSPCs cause damage to BMSCs F., who is also supported in part by an International Early Career that is partially responsible for disease manifestation and progres- Scientist grant of the Howard Hughes Medical Institute. We apolo- sion (Fig. 3). gize for omission of relevant literature due to space contraints. 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