Decidual Differentiation of Stromal Cells Promotes Proprotein Convertase 5/6 Expression and Lefty Processing

Lefty/Ebaf polypeptides, novel members of the TGF-β superfamily, are involved in endometrial differentiation and embryo implantation. Recently, we showed that, during undisturbed estrous cycle, lefty is present in mouse uterine horn primarily in a precursor form. Here, we show that decidual differentiation of endometrial stroma leads to increased lefty (∼3.1- to 3.6-fold in vivo and 5- to 8-fold in vitro) and processing of its precursor primarily to its long form. This event occurs on d 5 of pregnancy, and is paralleled by proprotein convertase (PC)5/6 up-regulation (∼6-fold increase for PC5A and 3-fold increase for PC5B) in decidualized uterine horn, independent of embryo implantation. Among the known convertases, only PC5/6A processes lefty to its long form. Taken together, the findings show that decidualized differentiation of stroma, which is a prerequisite for embryo implantation, leads to processing of lefty by PC5/6A.

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P–322 Addressing progesterone and cAMP signalling pathways for decidualization induction of endometrial stromal cells of patients with endometriosis

Human Reproduction ◽

10.1093/humrep/deab130.321 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

J Moyer ◽

D Dunj. Baston-Buest ◽

G Wennemuth ◽

A Bielfeld ◽

R Grümmer

Keyword(s):

Stromal Cells ◽

Day Treatment ◽

Embryo Implantation ◽

Flow Cytometric Analysis ◽

Prolactin Secretion ◽

In Vivo Model ◽

Endometrial Stromal Cells ◽

Simultaneous Application

Abstract Study question Which compounds/compound combinations are most effective in decidualization induction of endometrial stromal cells (ESCs) of patients with and without endometriosis? Summary answer Combination of compounds addressing different steps in the signalling cascade of decidualization induce decidualization more effectively than application of the individual compounds alone. What is known already Decidualization is the monthly recurring differentiation process of the ESCs in preparation for embryo implantation in human. Undifferentiated ESCs reveal an increased potential to proliferate and invade after retrograde menstruation. This may lead to the formation of ectopic lesions and the manifestation of the chronic gynaecological disease of endometriosis due to an impairment of the decidualization process. Study design, size, duration Compounds and compound combinations addressing the progesterone receptor- or the cAMP-mediated pathway were evaluated with regard to their own and their synergistic potential to induce decidualization of ESCs from women with (n = 10) and without (n = 10) endometriosis during a 6-day treatment. Participants/materials, setting, methods Human primary ESCs were isolated via enzymatic-mechanic digestion from eutopic endometrium from women with and without endometriosis and treated for 6 days in vitro with different progestins (progesterone, medoxyprogesterone acetate (MPA)), 8-Br-cAMP, forskolin, or phosphodiesterase (PDE)-inhibitor (Rolipram) alone or in combination. The degree of decidualization induction was quantified by morphological, biochemical (prolactin) and molecular (HAND2, FOXO1) parameters by means of ELISA, flow cytometric analysis, Realtime PCR and Western blot analysis. Main results and the role of chance After 6 days of treatment, decidualization was induced by forskolin as well as by 8-Br-cAMP whereas progestins or PDE alone hardly induced prolactin secretion by ESCs as a marker of decidualization. A change of morphology from undifferentiated fibroblast-like cells to rounded cells could be observed in parallel with the secretion of prolactin. Forskolin and 8-Br-cAMP-induced decidualization was significantly enhanced by MPA but not by progesterone. These effects were similar in ESCs from women with and without endometriosis. Moreover, forskolin-induced decidualization was significantly enhanced by simultaneous application of PDE. Interestingly, this effect was higher in cells of patients with endometriosis. An induction of decidualization in ESCs was associated with a parallel increase of the process-associated transcription factors HAND2 and FOXO1. This rise of transcription was markedly increased in combination with MPA but not with progesterone. Limitations, reasons for caution Endometrial tissue was obtained from women undergoing infertility treatment and thus may differ from the endometrium of fertile women. Results obtained from primary cells in vitro may not cover the in vivo situation in all respects. Wider implications of the findings: The results of this study provide baseline data for the development of a possible therapeutical approach to induce decidualization as a treatment option for endometriosis. Further research is required to determine the effectiveness of the in vitro tested compound combinations in an in vivo model. Trial registration number Not applicable

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P-322 Addressing progesterone and cAMP signalling pathways for decidualization induction of endometrial stromal cells of patients with endometriosis

Human Reproduction ◽

10.1093/humrep/deab127.077 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

J Moyer ◽

D Dunja Baston-Buest ◽

G Wennemuth ◽

A Bielfeld ◽

R Grümmer

Keyword(s):

Stromal Cells ◽

Day Treatment ◽

Embryo Implantation ◽

Flow Cytometric Analysis ◽

Prolactin Secretion ◽

In Vivo Model ◽

Endometrial Stromal Cells ◽

Simultaneous Application

Abstract Study question Which compounds/compound combinations are most effective in decidualization induction of endometrial stromal cells (ESCs) of patients with and without endometriosis? Summary answer Combination of compounds addressing different steps in the signalling cascade of decidualization induce decidualization more effectively than application of the individual compounds alone. What is known already Decidualization is the monthly recurring differentiation process of the ESCs in preparation for embryo implantation in human. Undifferentiated ESCs reveal an increased potential to proliferate and invade after retrograde menstruation. This may lead to the formation of ectopic lesions and the manifestation of the chronic gynaecological disease of endometriosis due to an impairment of the decidualization process. Study design, size, duration Compounds and compound combinations addressing the progesterone receptor- or the cAMP-mediated pathway were evaluated with regard to their own and their synergistic potential to induce decidualization of ESCs from women with (n = 10) and without (n = 10) endometriosis during a 6-day treatment. Participants/materials, setting, methods Human primary ESCs were isolated via enzymatic-mechanic digestion from eutopic endometrium from women with and without endometriosis and treated for 6 days in vitro with different progestins (progesterone, medoxyprogesterone acetate (MPA)), 8-Br-cAMP, forskolin, or phosphodiesterase (PDE)-inhibitor (Rolipram) alone or in combination. The degree of decidualization induction was quantified by morphological, biochemical (prolactin) and molecular (HAND2, FOXO1) parameters by means of ELISA, flow cytometric analysis, Realtime PCR and Western blot analysis. Main results and the role of chance After 6 days of treatment, decidualization was induced by forskolin as well as by 8-Br-cAMP whereas progestins or PDE alone hardly induced prolactin secretion by ESCs as a marker of decidualization. A change of morphology from undifferentiated fibroblast-like cells to rounded cells could be observed in parallel with the secretion of prolactin. Forskolin and 8-Br-cAMP-induced decidualization was significantly enhanced by MPA but not by progesterone. These effects were similar in ESCs from women with and without endometriosis. Moreover, forskolin-induced decidualization was significantly enhanced by simultaneous application of PDE. Interestingly, this effect was higher in cells of patients with endometriosis. An induction of decidualization in ESCs was associated with a parallel increase of the process-associated transcription factors HAND2 and FOXO1. This rise of transcription was markedly increased in combination with MPA but not with progesterone. Limitations, reasons for caution Endometrial tissue was obtained from women undergoing infertility treatment and thus may differ from the endometrium of fertile women. Results obtained from primary cells in vitro may not cover the in vivo situation in all respects. Wider implications of the findings The results of this study provide baseline data for the development of a possible therapeutical approach to induce decidualization as a treatment option for endometriosis. Further research is required to determine the effectiveness of the in vitro tested compound combinations in an in vivo model. Trial registration number not applicable

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Endometrial pyruvate kinase M2 is essential for decidualization during early pregnancy

Journal of Endocrinology ◽

10.1530/joe-19-0553 ◽

2020 ◽

Vol 245 (3) ◽

pp. 357-368 ◽

Cited By ~ 2

Author(s):

Yan Su ◽

Sujuan Guo ◽

Chunyan Liu ◽

Na Li ◽

Shuang Zhang ◽

...

Keyword(s):

Cell Proliferation ◽

Pyruvate Kinase ◽

Early Pregnancy ◽

Stromal Cells ◽

Embryo Implantation ◽

Pyruvate Kinase M2 ◽

Ishikawa Cells ◽

Implantation Sites

Embryo implantation is essential for normal pregnancy. Decidualization is known to facilitate embryo implantation and maintain pregnancy. Uterine stromal cells undergo transformation into decidual cells after embryo attachment to the endometrium. Pyruvate kinase M2 (PKM2) is a rate limiting enzyme in the glycolysis process which catalyzes phosphoenolpyruvic acid into pyruvate. However, little is known regarding the role of PKM2 during endometrial decidualization. In this study, PKM2 was found to be mainly located in the uterine glandular epithelium and luminal epithelium on day 1 and day 4 of pregnancy and strongly expressed in the decidual zone after embryo implantation. PKM2 was dramatically increased with the onset of decidualization. Upon further exploration, PKM2 was found to be more highly expressed at the implantation sites than at the inter-implantation sites on days 5 to 7 of pregnancy. PKM2 expression was also significantly increased after artificial decidualization both in vivo and in vitro. After PKM2 expression was knocked down by siRNA, the number of embryo implantation sites in mice on day 7 of pregnancy was significantly reduced, and the decidualization markers BMP2 and Hoxa10 were also obviously downregulated in vivo and in vitro. Downregulated PKM2 could also compromise cell proliferation in primary endometrial stromal cells and in Ishikawa cells. The migration rate of Ishikawa cells was also obviously suppressed by si-PKM2 according to the wound healing assay. In conclusion, PKM2 might play an important role in decidualization during early pregnancy, and cell proliferation might be one pathway for PKM2 regulated decidualization.

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211. Proteomic identification of caldesmon as one of the physiological substrates of proprotein convertase 6 during decidualisation

Reproduction Fertility and Development ◽

10.1071/srb08abs211 ◽

2008 ◽

Vol 20 (9) ◽

pp. 11

Author(s):

B. M. Hardman ◽

L. M. Kilpatrick ◽

A. N. Stephens ◽

J. I. C. Chen ◽

P. Stanton ◽

...

Keyword(s):

Stromal Cells ◽

Hypoxia Inducible Factor ◽

Immunohistochemical Analysis ◽

Spectrometric Analysis ◽

Structural Protein ◽

Proprotein Convertase ◽

Endometrial Stromal Cells ◽

Decidual Cells

We have previously demonstrated that proprotein convertase 5/6 (PC6), a member of the proprotein convertase (PC) family, is a critical endometrial factor for implantation. PC6 is upregulated in the endometrium specifically at implantation in association with epithelial differentiation (in human and monkey) and stromal cell decidualisation (in the mouse, human and monkey). Knockdown of endometrial PC6 during early pregnancy in mice in vivo led to complete failure of implantation, while blocking of PC6 production in human endometrial stromal cells in vitro inhibited decidualisation. PCs convert a range of precursor proteins of important functions into their bioactive forms; they are thus regarded as critical ‘master switch’ molecules. We hypothesise that PC6 exerts its roles in the endometrium by regulating proteins of diverse functions essential for implantation. In this study, we utilised proteomic technology and aimed to identify proteins that are specifically cleaved by PC6 in human endometrial stromal cells (HESC) during decidualisation. HESC were decidualised with cyclic AMP, the cell lysates were treated with and without recombinant human PC6-A (rPC6-A), and the 2D Differential in Gel Electrophoresis (2D DiGE) protein profiles were compared between the two treatments. We identified several proteins which were differentially cleaved following the addition of rPC6-A. Mass spectrometric analysis confirmed that the most abundant of these were caldesmon, tropomyosin-2, tropomyosin-4, hypoxia Inducible factor-1 and chloride intracellular channel-1. These proteins showed spot shifts in hPC6-A treated HESC lysates consistent with hPC6-A cleavage. western blot analysis confirmed the specific cleavage of caldesmon by PC6 in HESCs, and immunohistochemical analysis showed co-localisation of caldesmon and PC6 in decidual cells in human endometrial tissue. Given that caldesmon is a structural protein previously found to be involved in actin filament reorganisation, our results strongly suggest that PC6 is a mediator of structural remodelling of stromal cells during decidualisation in the endometrium.

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Pharmacological Preconditioning Improves the Viability and Proangiogenic Paracrine Function of Hydrogel-Encapsulated Mesenchymal Stromal Cells

Stem Cells International ◽

10.1155/2021/6663467 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Francesco K. Touani ◽

Melanie Borie ◽

Feryel Azzi ◽

Dominique Trudel ◽

Nicolas Noiseux ◽

...

Keyword(s):

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Wound Closure ◽

Fold Increase ◽

Thermosensitive Hydrogel ◽

Injectable Scaffold ◽

Cell Pretreatment ◽

Pharmacological Preconditioning

The efficacy of cell therapy is limited by low retention and survival of transplanted cells in the target tissues. In this work, we hypothesize that pharmacological preconditioning with celastrol, a natural potent antioxidant, could improve the viability and functions of mesenchymal stromal cells (MSC) encapsulated within an injectable scaffold. Bone marrow MSCs from rat (rMSC) and human (hMSC) origin were preconditioned for 1 hour with celastrol 1 μM or vehicle (DMSO 0.1% v / v), then encapsulated within a chitosan-based thermosensitive hydrogel. Cell viability was compared by alamarBlue and live/dead assay. Paracrine function was studied first by quantifying the proangiogenic growth factors released, followed by assessing scratched HUVEC culture wound closure velocity and proliferation of HUVEC when cocultured with encapsulated hMSC. In vivo, the proangiogenic activity was studied by evaluating the neovessel density around the subcutaneously injected hydrogel after one week in rats. Preconditioning strongly enhanced the viability of rMSC and hMSC compared to vehicle-treated cells, with 90% and 75% survival versus 36% and 58% survival, respectively, after 7 days in complete media and 80% versus 64% survival for hMSC after 4 days in low serum media ( p < 0.05 ). Celastrol-treated cells increased quantities of proangiogenic cytokines compared to vehicle-pretreated cells, with a significant 3.0-fold and 1.8-fold increase of VEGFa and SDF-1α, respectively ( p < 0.05 ). The enhanced paracrine function of preconditioned MSC was demonstrated by accelerated growth and wound closure velocity of injured HUVEC monolayer ( p < 0.05 ) in vitro. Moreover, celastrol-treated cells, but not vehicle-treated cells, led to a significant increase of neovessel density in the peri-implant region after one week in vivo compared to the control (blank hydrogel). These results suggest that combining cell pretreatment with celastrol and encapsulation in hydrogel could potentiate MSC therapy for many diseases, benefiting particularly ischemic diseases.

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Progesterone-induced RNA Hand2os1 regulates decidualization in mice uteri

Reproduction ◽

10.1530/rep-19-0401 ◽

2020 ◽

Vol 159 (3) ◽

pp. 303-314

Author(s):

Yanni Jia ◽

Rui Cai ◽

Tong Yu ◽

Ruixue Zhang ◽

Shouqin Liu ◽

...

Keyword(s):

Stromal Cells ◽

Embryo Implantation ◽

Pregnant Mouse ◽

Differentially Expressed ◽

Sequencing Analysis ◽

Functional Roles ◽

Decidual Cells ◽

Functional Clustering Analysis

Decidualization is a critical process for successful embryo implantation and subsequent placenta formation. The characterization and physiological function of lncRNA during decidualization remain largely unknown. In the present study, we conducted RNA-sequencing analysis to compare gene expression between decidua of days 6 and 8, and normal pregnant endometrium (day 4). A total of 2332 high-confidence putative lncRNA transcripts were expressed. Functional clustering analysis of cis and trans lncRNA targets showed that differentially expressed lncRNAs may regulate multiple gene ontology terms and pathways that have important functions in decidualization. Subsequent analyses using qRT-PCR validated that eight of all lncRNAs were differentially regulated in mice uteri during decidualization, both in vivo and in vitro. Furthermore, we showed that differentially expressed lncRNA of Hand2os1 was specifically detected in stromal cells on days 2 to 5 of pregnancy and was strongly upregulated in decidual cells on days 6–8 of pregnancy. Similarly, Hand2os1 expression was also strongly expressed in decidualized cells following artificial decidualization, both in vivo and in vitro. In uterine stromal cells, P4 was able to significantly upregulate the expression of Hand2os1, but upregulation was impeded by RU486, whereas E2 appeared to have no regulating effect on Hand2os1 expression. Concurrently, Hand2os1 significantly promoted the decidual process in vitro and dramatically increased decidualization markers Prl8a2 and Prl3c1. Our results provide a valuable catalog for better understanding of the functional roles of lncRNAs in pregnant mouse uteri, as it relates to decidualization.

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Differential expression and regulation of Cryab in mouse uterus during preimplantation period

Reproduction ◽

10.1530/rep-13-0042 ◽

2013 ◽

Vol 145 (6) ◽

pp. 577-585 ◽

Cited By ~ 12

Author(s):

Xue-Chao Tian ◽

Qu-Yuan Wang ◽

Dang-Dang Li ◽

Shou-Tang Wang ◽

Zhan-Qing Yang ◽

...

Keyword(s):

Real Time ◽

Stromal Cells ◽

Real Time Pcr ◽

Embryo Implantation ◽

Mouse Uterus ◽

High Level ◽

Implantation Period

The aim of this study was to examine the expression and regulation of the crystallin, alpha B (Cryab) gene in mouse uterus during the peri-implantation period by in situ hybridization and real-time PCR. There was no detectable Cryab mRNA signal on days 1–4 of pregnancy. On day 5 of pregnancy when embryo implanted, a high level of Cryab mRNA signal was found in the subluminal stroma surrounding the implanting blastocyst. On days 6–8, Cryab mRNA was strongly expressed in the primary decidua. By real-time PCR, a high level of Cryab expression was detected on days 7 and 8 of pregnancy, although Cryab expression was seen from days 1 to 8. Under in vivo and in vitro artificial decidualization, Cryab expression was significantly elevated. Compared with the progesterone-primed delayed implantation uterus, a high level of Cryab mRNA expression was observed in estrogen-activated implantation uterus. In the uterine stromal cells, cAMP, estrogen, and progesterone could induce the expression of Cryab gene. In the ovariectomized mouse uterus, estrogen could also induce the expression of Cryab while progesterone inhibited its expression. Our data suggest that Cryab may play an important role during mouse embryo implantation and decidualization and that estrogen and progesterone can regulate the expression of Cryab gene.

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Human endometrial stromal cells inhibit the pro-angiogenic stimulus of hCG in vitro

Reproduction ◽

10.1530/rep-19-0559 ◽

2020 ◽

Vol 160 (5) ◽

pp. 673-684

Author(s):

Marcia Riboldi ◽

Ivonne Nazir ◽

Belén Jara ◽

Felipe Argandoña ◽

Cecilia Valencia ◽

...

Keyword(s):

Endothelial Cells ◽

Stromal Cells ◽

Ovarian Stimulation ◽

Embryo Implantation ◽

Primary Cultures ◽

In Vivo Model ◽

Endometrial Stromal Cells ◽

Angiogenic Potential

During embryo implantation, endometrial angiogenesis is regulated by signals originating from the endometrium itself and the developing embryo. It has been suggested that hCG may play a pro-angiogenic role; therefore, we sought to understand its regulatory role in blood vessel formation in human endometrium using in vivo and in vitro models. In the in vivo model, we screened 16 angiogenesis-related transcripts in the endometrium upon intrauterine administration of hCG. Oocyte donors were recruited and during their controlled ovarian stimulation cycle received a single dose of hCG or vehicle on the day of oocyte pick up during a cycle of ovarian stimulation. One hour before obtaining an endometrial sample, women received an intrauterine administration of vehicle or hCG (500, 1500 and 5000 IU). Transcript and protein analysis showed that MMP3 and VEGFA increased, whereas TIMP1 decreased. The in vitro analysis studied the angiogenic potential of conditioned medium (CM) from primary cultures of human endometrial stromal cells (ESC) stimulated with hCG. Using a 2D and 3D in vitro angiogenesis assays, our results indicate that CM from ESC almost completely inhibits the capillary-like structure formation in endothelial cells, overriding the pro-angiogenic effect of hCG; and this inhibition due to secreted factors present in CM specifically reduced the migration potential of endothelial cells. In conclusion, the endometrial stromal milieu seems to modulate the direct pro-angiogenic effects of hCG on endothelial cells during embryo implantation.

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Inhibition of TPPP3 attenuates β-catenin/NF-κB/COX-2 signaling in endometrial stromal cells and impairs decidualization

Journal of Endocrinology ◽

10.1530/joe-18-0459 ◽

2019 ◽

Vol 240 (3) ◽

pp. 417-429 ◽

Cited By ~ 6

Author(s):

Vinay Shukla ◽

Jyoti Bala Kaushal ◽

Pushplata Sankhwar ◽

Murli Manohar ◽

Anila Dwivedi

Keyword(s):

Stromal Cells ◽

Embryo Implantation ◽

Nuclear Accumulation ◽

Decidual Cell ◽

Endometrial Stromal Cells ◽

Cox 2 ◽

Sirna Knockdown

Embryo implantation and decidualization are critical events that occur during early pregnancy. Decidualization is synchronized by the crosstalk of progesterone and the cAMP signaling pathway. Previously, we confirmed the role of TPPP3 during embryo implantation in mice, but the underlying role and mechanism of TPPP3 in decidualization has not yet been understood. The current study was aimed to investigate the role of TPPP3 in decidualization in vivo and in vitro. For in vivo experiments, decidual reaction was artificially induced in the uteri of BALB/c mice. TPPP3 was found to be highly expressed during decidualization, whereas in the uteri receiving TPPP3 siRNA, decidualization was suppressed and the expression of β-catenin and decidual marker prolactin was reduced. In human endometrium, TPPP3 protein was found to be predominantly expressed in the mid-secretory phase (LH+7). In the primary culture of human endometrial stromal cells (hESCs), TPPP3 siRNA knockdown inhibited stromal-to-decidual cell transition and decreased the expression of the decidualization markers prolactin and IGFBP-1. Immunofluorescence and immunoblotting experiments revealed that TPPP3 siRNA knockdown suppressed the expression of β-catenin, NF-κB and COX-2 in hESCs during decidualization. TPPP3 inhibition also decreased NF-kB nuclear accumulation in hESCs and suppressed NF-κB transcriptional promoter activity. COX-2 expression was significantly decreased in the presence of a selective NF-kB inhibitor (QNZ) implicating that NF-kB is involved in COX-2 expression in hESCs undergoing decidualization. TUNEL assay and FACS analysis revealed that TPPP3 knockdown induced apoptosis and caused loss of mitochondrial membrane potential in hESCs. The study suggested that TPPP3 plays a significant role in decidualization and its inhibition leads to the suppression of β-catenin/NF-κB/COX-2 signaling along with the induction of mitochondria-dependent apoptosis.

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Bone marrow remodelling supports hematopoiesis in response to immune thrombocytopenia progression

Blood Advances ◽

10.1182/bloodadvances.2020003887 ◽

2021 ◽

Author(s):

Oliver J. Herd ◽

Gulab Fatima Rani ◽

James P Hewitson ◽

Karen Hogg ◽

Andrew P Stone ◽

...

Keyword(s):

Bone Marrow ◽

Stromal Cells ◽

Immune Thrombocytopenia ◽

Fold Increase ◽

In Vivo Model ◽

Hematopoietic Stem ◽

Cell Assays ◽

Autoimmune Condition

Immune thrombocytopenia (ITP) is an acquired autoimmune condition characterized by both reduced platelet production and the destruction of functionally normal platelets by sustained attack from the immune system. However, the effect of prolonged ITP on the more immature hematopoietic progenitors remains an open area of investigation. Using a murine in vivo model of extended ITP, we reveal that ITP progression drives considerable progenitor expansion and bone marrow (BM) remodelling. Single cell assays using Lin-Sca1+c-Kit+CD48-CD150+ long-term hematopoietic stem cells (LT-HSCs) revealed elevated LT-HSC activation and proliferation in vitro. However, the increased activation did not come at the expense of LT-HSC functionality as measured by in vivo serial transplantations. ITP progression was associated with considerable BM vasodilation and angiogenesis, as well as a 2-fold increase in local production of CXCL12; a cytokine essential for LT-HSC function and BM homing expressed at high levels by LepR+ BM stromal cells. This was associated with a 1.5-fold increase in LepR+ BM stromal cells and a 5.5-fold improvement in progenitor homing to the BM. Whereas the increase in stromal cells was transient and reverted back to baseline after platelet count returned to normal, vasculature changes in the BM persisted. Together, these studies demonstrate that LT-HSCs expand in response to ITP, and that LT-HSC functionality during sustained hematopoietic stress is maintained through an adapting BM microenvironment.

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