scholarly journals Impact of Syndecan-2-Selected Mesenchymal Stromal Cells on the Early Onset of Diabetic Cardiomyopathy in Diabetic db/db Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Kathleen Pappritz ◽  
Fengquan Dong ◽  
Kapka Miteva ◽  
Arpad Kovacs ◽  
Muhammad El-Shafeey ◽  
...  
Keyword(s):  
Experimental Model ◽  
Mesenchymal Stromal Cells ◽  
Diabetic Cardiomyopathy ◽  
Stromal Cells ◽  
Early Onset ◽  
Left Ventricular ◽  
Guanosine Monophosphate ◽  
Lv Function ◽  
Protein Distribution ◽  
The Impact

Background: Mesenchymal stromal cells (MSCs) are an attractive cell type for cell therapy given their immunomodulatory, anti-fibrotic, and endothelial-protective features. The heparin sulfate proteoglycan, syndecan-2/CD362, has been identified as a functional marker for MSC isolation, allowing one to obtain a homogeneous cell product that meets regulatory requirements for clinical use. We previously assessed the impact of wild-type (WT), CD362−, and CD362+ MSCs on local changes in protein distribution in left ventricular (LV) tissue and on LV function in an experimental model of early-onset diabetic cardiomyopathy. The present study aimed to further explore their impact on mechanisms underlying diastolic dysfunction in this model.Materials: For this purpose, 1 × 106 WT, CD362−, or CD362+ MSCs were intravenously (i.v.) injected into 20-week-old diabetic BKS.Cg-m+/+Leprdb/BomTac, i.e., db/db mice. Control animals (db+/db) were injected with the equivalent volume of phosphate-buffered saline (PBS) alone. After 4 weeks, mice were sacrificed for further analysis.Results: Treatment with all three MSC populations had no impact on blood glucose levels in db/db mice. WT, CD362−, and CD362+ MSC application restored LV nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) levels in db/db mice, which correlated with a reduction in cardiomyocyte stiffness. Furthermore, all stromal cells were able to increase arteriole density in db/db mice. The effect of CD362+ MSCs on NO and cGMP levels, cardiomyocyte stiffness, and arteriole density was less pronounced than in mice treated with WT or CD362− MSCs. Analysis of collagen I and III protein expression revealed that fibrosis had not yet developed at this stage of experimental diabetic cardiomyopathy. All MSCs reduced the number of cardiac CD3+ and CD68+ cells in db/db mice, whereas only splenocytes from CD362−- and CD362+-db/db mice exhibited a lower pro-fibrotic potential compared to splenocytes from db/db mice.Conclusion: CD362+ MSC application decreased cardiomyocyte stiffness, increased myocardial NO and cGMP levels, and increased arteriole density, although to a lesser extent than WT and CD362− MSCs in an experimental model of early-onset diabetic cardiomyopathy without cardiac fibrosis. These findings suggest that the degree in improvement of cardiomyocyte stiffness following CD362+ MSC application was insufficient to improve diastolic function.

scholarly journals Immunomodulatory Effects of Mesenchymal Stromal Cells Revisited in the Context of Inflammatory Cardiomyopathy

2013 ◽  
Vol 2013 ◽  
pp. 1-16 ◽  
Author(s):  
Kapka Miteva ◽  
Sophie Van Linthout ◽  
Hans-Dieter Volk ◽  
Carsten Tschöpe
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Current Knowledge ◽  
Left Ventricular ◽  
Inflammatory Cardiomyopathy ◽  
Long Term Outcomes ◽  
Paracrine Effects ◽  
Cellular Transplantation ◽  
The Impact

Myocarditis is a common inflammatory cardiomyopathy, associated with cardiomyocyte apoptosis, which can lead to chronic left ventricular dysfunction. Under conventional heart failure therapy, inflammatory cardiomyopathy typically has a progressive course, indicating a need for alternative therapeutic strategies to improve long-term outcomes. Experimental and clinical studies consistently support the application of cellular transplantation as a strategy to improve myocardial function. Mesenchymal stromal cells (MSCs) mediate distinct paracrine effects supporting endogenous regeneration, but most important are their remarkable immunoregulatory properties. In this review, an overview of current knowledge on immunopathology in myocarditis will be given. Furthermore, current research regarding the immunomodulatory properties of MSCs in the context of myocarditis will be discussed. Finally, the impact of MSC priming by the environment on their functionality and the advantages of systemic administration of MSCs under myocarditis are outlined.

scholarly journals Alloreactive Immune Response Associated to Human Mesenchymal Stromal Cells Treatment: A Systematic Review

2021 ◽  
Vol 10 (13) ◽  
pp. 2991
Author(s):  
Raquel Sanabria-de la Torre ◽  
María I. Quiñones-Vico ◽  
Ana Fernández-González ◽  
Manuel Sánchez-Díaz ◽  
Trinidad Montero-Vílchez ◽  
...  
Keyword(s):  
Systematic Review ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Immune Rejection ◽  
Human Mesenchymal Stromal Cells ◽  
Immunological Profile ◽  
Tolerability Data ◽  
Donor Specific Antibodies ◽  
The Impact ◽  
Hla Mismatches

The well-known immunomodulatory and regenerative properties of mesenchymal stromal cells (MSCs) are the reason why they are being used for the treatment of many diseases. Because they are considered hypoimmunogenic, MSCs treatments are performed without considering histocompatibility barriers and without anticipating possible immune rejections. However, recent preclinical studies describe the generation of alloantibodies and the immune rejection of MSCs. This has led to an increasing number of clinical trials evaluating the immunological profile of patients after treatment with MSCs. The objective of this systematic review was to evaluate the generation of donor specific antibodies (DSA) after allogeneic MSC (allo-MSC) therapy and the impact on safety or tolerability. Data from 555 patients were included in the systematic review, 356 were treated with allo-MSC and the rest were treated with placebo or control drugs. A mean of 11.51% of allo-MSC-treated patients developed DSA. Specifically, 14.95% of these patients developed DSA and 6.33% of them developed cPRA. Neither the production of DSA after treatment nor the presence of DSA at baseline (presensitization) were correlated with safety and/or tolerability of the treatment. The number of doses administrated and human leucocyte antigen (HLA) mismatches between donor and recipient did not affect the production of DSA. The safety of allo-MSC therapy has been proved in all the studies and the generation of alloantibodies might not have clinical relevance. However, there are very few studies in the area. More studies with adequate designs are needed to confirm these results.

Abstract 16485: The Nitroxyl Donor 1-Nitrosocyclohexyl Acetate Limits Cardiac Superoxide Upregulation and Diastolic Dysfunction in a Mouse Model of Diabetic Cardiomyopathy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Rebecca H Ritchie ◽  
Nga Cao ◽  
Yung George Wong ◽  
Sarah Rosli ◽  
Helen Kiriazis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Diastolic Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Ex Vivo ◽  
Systolic Function ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Lv Diastolic Dysfunction ◽  
The Impact

Nitroxyl (HNO), a redox congener of NO•, is a novel regulator of cardiovascular function combining vasodilator and positive inotropic properties. Our previous studies have demonstrated these properties occur concomitantly in the intact heart; HNO moreover also exhibits antihypertrophic and superoxide-suppressing actions. HNO donors may thus offer favorable actions in heart failure. The impact of chronic HNO donor administration has however yet to be reported in this context. We tested the hypothesis that the HNO donor 1-nitrosocyclohexyl acetate (1-NCA) limits cardiomyocyte hypertrophy and left ventricular (LV) diastolic dysfunction in a mouse model of diabetic cardiomyopathy in vivo. Male 6 week-old FVB/N mice received either streptozotocin (55 mg/kg/day i.p. for 5 days, n=17), to induce type 1 diabetes, or citrate vehicle (n=16). After 4 weeks of hyperglycemia, mice were allocated to 1-NCA therapy (83mg/kg/day i.p.) or vehicle, and followed for a further 4 weeks. As shown in the table, blood glucose was unaffected by 1-NCA. LV diastolic dysfunction was evident in diabetic mice, measured as echocardiography-derived A wave velocity, deceleration time and E:A ratio; LV systolic function was preserved. Diabetes-induced diastolic dysfunction was accompanied by increased LV cardiomyocyte size, hypertrophic and pro-fibrotic gene expression, and upregulation of LV superoxide. These characteristics of diabetic cardiomyopathy were largely prevented by 1-NCA treatment. Selectivity of 1-NCA as a donor of HNO versus NO• was demonstrated by the sensitivity of the coronary vasodilation response of 1-NCA to the HNO scavenger L-cysteine (4mM), but not to the NO• scavenger hydroxocobalamin (50μM), in the normal rat heart ex vivo (n=3-7). Collectively, our studies provide the first evidence that HNO donors may represent a promising new strategy for the treatment of diabetic cardiomyopathy, and implies their therapeutic efficacy in settings of chronic heart failure.

Impact of Valve Surgery on Serum Osteopontin Levels in Patients with Mitral Regurgitation

Cardiology ◽  
2015 ◽  
Vol 130 (2) ◽  
pp. 82-86
Author(s):  
H.M. Gunes ◽  
G.B. Guler ◽  
E. Guler ◽  
G.G. Demir ◽  
S. Hatipoglu ◽  
...  
Keyword(s):  
Mitral Regurgitation ◽  
Left Ventricular ◽  
Valve Surgery ◽  
Lv Function ◽  
Vena Contracta ◽  
Atherosclerotic Lesions ◽  
Lv Dysfunction ◽  
Echocardiographic Parameters ◽  
Artery Disease ◽  
The Impact

Objective: Osteopontin (OPN), a sialoprotein present within atherosclerotic lesions, especially in calcified plaques, is linked to the progression of coronary artery disease and heart failure. We assessed the impact of valve surgery on serum OPN and left ventricular (LV) function in patients with mitral regurgitation (MR). Methods: Thirty-two patients with severe MR scheduled for surgery were included in the study. Echocardiography markers were assessed preoperatively and at 3 months following the surgery and matched with the serum OPN levels. Results: Valve surgery was associated with a reduction of the ejection fraction (EF) from 55.2 ± 6.3 to 48.8 ± 7.1% after surgery, p < 0.001. Following surgery, the OPN level was significantly higher than preoperatively (mean 245, range 36-2,284 ng/ml vs. 76, 6-486 ng/ml, p = 0.007). Preoperative OPN exhibited a slight negative correlation with the EF (r = -0.35, p = 0.04), and a moderate correlation with vena contracta (r = -0.38, p = 0.02). There were no other meaningful correlations between conventional echocardiographic parameters and OPN. Conclusion: Following valve surgery due to severe MR, patients exhibited a decrease in EF and an increase in OPN levels. The assessment of preoperative OPN failed to strongly predict probable LV dysfunction.

Abstract 15172: Murf1 Inhibitor Embl205 is a New Approach for Treatment of Heart Failure With Preserved Ejection Fraction in an Animal Model

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Anett Jannasch ◽  
Antje Schauer ◽  
Virginia Kirchhoff ◽  
Runa Draskowsi ◽  
Claudia Dittfeld ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Pressure ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Skeletal Muscle Atrophy ◽  
Lv Function ◽  
Preserved Ejection Fraction ◽  
The Impact ◽  
Peak Gradient

Background: The novel MuRF1 inhibitor EMBL205 attenuates effectively developing skeletal muscle atrophy and dysfunction in animals with heart failure with preserved ejection fraction (HFpEF, ZSF1 rat model). The impact of EMBL205 on myocardial function in the HFpEF setting is currently unknown and was evaluated in ZSF1 rats. Methods: 20 wks-old female obese ZSF1 rats received EMBL205 (12 wks, conc. of 0.1% in chow; HFpEF-EMBL205). Age-matched untreated lean (con) and obese (HFpEF) ZSF1 rats served as controls. At 32 wks of age left ventricular (LV)-, aortic valve (AV) function and LV end diastolic pressure (LVEDP) was determined by echocardiography and invasive hemodynamic measurements. LV expression of collagen 1A (Col1A) and 3A (Col3A) was assessed by qRT-PCR, MMP2 expression was obtained by zymography and perivascular fibrosis was quantified in histological sections. Results: Development of HFpEF in ZSF1 obese animals is associated with cardiac enlargement and hypertrophy, as evident by increased myocardial weight, an increase in end diastolic volume (EDV) and LV anterior and posterior wall diameters. Diastolic LV-function is disturbed with elevation of E/é, an increased LVEDP and a preserved LV ejection fraction. AV peak velocity and peak gradient are significantly increased and AV opening area (AVA) significantly decreased. Col1A and Col3A expression are increased in HFpEF animals. EMBL205 treatment results in a significant reduction of myocardial weight and a trend towards lower EDV compared to HFpEF group. EMBL205 attenuates the increase in E/é, LVEDP, AV peak gradient and the decrease of AVA. EMBL205 significantly reduces Col3A expression and a trend for Col1A expression is seen. Increased perivascular fibrosis and MMP2 expression in HFpEF is extenuated by EMBL205 treatment (table 1). Conclusions: Application of EMBL205 attenuated the development of pathological myocardial alterations associated with HFpEF in ZSF1rats due to antifibrotic effects.

Abstract WMP37: Methodological Quality and Meta-Analysis of Animal Studies of Mesenchymal Stromal Cells for Ischemic Stroke

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Kate Xie* ◽  
Quynh Vu* ◽  
Mark Eckert ◽  
Weian Zhao ◽  
Steven C Cramer
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Effect Size ◽  
Stromal Cells ◽  
Methodological Quality ◽  
Meta Analysis ◽  
Quality Score ◽  
Behavioral Effects ◽  
Behavioral Measure ◽  
Routes Of Administration ◽  
The Impact

INTRODUCTION: Mesenchymal stromal cells (MSC) are multipotent cells that support numerous restorative processes after stroke. The ease of isolation and immunoprivileged status of MSC have stimulated numerous preclinical stroke studies. We performed a meta-analysis to estimate study quality, size of behavioral effects, and the impact of variables such as timing of MSC administration in relation to stroke onset. METHODS: Studies of MSC and stroke were identified through PubMed and Web of Science. Studies of hemorrhage, not in English, or using modified MSC were excluded. A Quality Score was determined for each study, estimating methodological quality using 10 criteria derived from STAIR guidelines, with higher Quality Scores reflecting greater compliance with issues such as randomization and outcome blinding. Outcome data extracted for MSC and control arms were used to derive estimates of effect size using Cohen’s d. RESULTS: A total of 46 studies met criteria, with 39 studying rats, 6 mice, and 1 primates. There were 61 treatment groups, as some studies had >1 independent MSC treatment arms; MSC were introduced intravenously in 41, intracerebrally in 15, and intraarterially in 6. MSC source was rat in 24, human in 16, and mouse in 6. Time of MSC administration ranged from 5 weeks pre- to 1 month post-stroke. MSC dose ranged from 1x10^4 to 3.25x10^7. The median Quality Score was 6 (IQR 5-7). Quality Score was not related to time of MSC administration relative to stroke or to behavioral effect size. Median effect size was 2.05 for the Modified Neurological Severity Scale (n=23), 1.88 for Adhesive Removal Test (n=19), and 2.70 for the Rotarod Test (n=14). Effect sizes were substantial across all routes of administration and differed only for the mNSS (p<0.04), favoring the IC route. Effect size did not vary with time of MSC administration relative to stroke for any behavioral measure. CONCLUSIONS: The quality of preclinical MSC stroke studies has generally been good. MSC consistently provide very large behavioral benefits, across scales and routes of administration. The magnitude of behavioral effects was not related to the Quality Score or to the time of MSC administration relative to stroke. These findings support translation of MSC to human trials.

The impact of mitochondria and reactive oxygen species on the proliferation of human amniotic mesenchymal stromal cells

2018 ◽  
Vol 1859 ◽  
pp. e45
Author(s):  
Sergiu Dumitrescu ◽  
Adelheid Weidinger ◽  
Asmita Banerjee ◽  
Susanne Wolbank ◽  
Karlheinz Hilber ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
The Impact

scholarly journals Characterization of the Hematopoietic Supporting Activity of Osteoblasts Derived from Bone Marrow Mesenchymal Stromal Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4358-4358
Author(s):  
Manal Alsheikh ◽  
Roya Pasha ◽  
Nicolas Pineault
Keyword(s):  
Bone Marrow ◽  
Osteogenic Differentiation ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Conflicts Of Interest ◽  
Soluble Factors ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
The Impact ◽  
Myeloid Progenitors

Abstract Osteoblasts (OST) found within the endosteal niche are important regulators of Hematopoietic Stem and Progenitor Cells (HSPC) under steady state and during hematopoietic reconstitution. OST are derived from mesenchymal stromal cells (MSC) following osteogenic differentiation. MSC and OST secrete a wide array of soluble factors that sustain hematopoiesis. Recently, we showed that media conditioned with OST derived from MSC (referred as M-OST) after 6 days of osteogenic differentiation were superior to MSC conditioned media (CM) for the expansion of cord blood (CB) progenitors, and CB cells expanded with M-OST CM supported a more robust engraftment of platelets in NSG mice after transplantation. These findings raised the possibility that M-OST could be superior to MSC for the ex vivoexpansion HSPC. In this study, we set out to test the hypothesis that the growth modulatory activity of M-OST would vary as a function of their maturation status. The objectives were to first monitor the impact of M-OST differentiation and maturation status on the expression of soluble factors that promote HSPC expansion and in second, to investigate the capacity of M-OST CMs prepared from M-OST at distinct stages of differentiation to support the expansion and differentiation of HSPCs in culture. M-OST at distinct stages of differentiation were derived by culturing bone marrow MSC in osteogenic medium for various length of time (3 to 21 days). All CB CD34+ enriched (92±7% purity) cell cultures were done with serum free media conditioned or not with MSC or M-OST and supplemented with cytokines SCF, TPO and FL. We first confirmed the progressive differentiation and maturation of M-OST as a function of osteogenic culture length, which was evident by the induction of the osteogenic transcription factors Osterix, Msx2 and Runx2 mRNAs, the gradual increase in osteopontin and alkaline phosphatase positive cells and quantitative increases in calcium deposit. Next, we investigated the expression in MSC and M-OSTs of genes known to collaborate for the expansion of HSPCs by Q-PCR. Transcript copy numbers for IGFBP-2 increased swiftly during osteogenic differentiation, peaking at day-3 (˃100-fold vs MSC, n=2) and returning below MSC level by day-21. In contrast, ANGPTL members (ANGPTL-1, -2, -3 and -5) remained superior in M-OSTs throughout osteogenic differentiation with expression levels peaking around day 6 (n=2). Next, we tested the capacity of media conditioned with primitive (day-3, -6), semi-mature (day-10, -14) and mature M-OST (day-21) to support the growth of CB cells. All M-OST CMs increased (p˂0.03) the growth of total nucleated cells (TNC) after 6 days of culture compared to non-conditioned medium used as control (mean 2.0-fold, n=4). Moreover, there was a positive correlation between cell growth and M-OST maturation status though differences between the different M-OST CMs tested were not significant. The capacity of M-OST CMs to increase (mean 2-fold, n=4) the expansion of CD34+ cells was also shared by all M-OST CMs (p˂0.05), as supported by significant increases with immature day-3 (mean ± SD of 18 ± 6, p˂0.02) and mature day-21 M-OST CMs (14 ± 5, p˂0.05) vs. control (8 ± 3, n=4). Conversely, expansions of TNC and CD34+ cells in MSC CM cultures were in-between that of control and M-OST CMs cultures. Interestingly, M-OST CMs also modulated the expansion of the HSPC compartment. Indeed, while the expansion of multipotent progenitors defined as CD34+CD45RA+ was promoted in control culture (ratio of 4.5 for CD34+CD45RA+/CD34+CD45RA- cells), M-OST CMs supported greater expansion of the more primitive CD34+CD45RA- HSPC subpopulation reducing the ratio to 3.3±0.4 for M-OST cultures (cumulative mean of 10 cultures, n=2). Moreover, the expansions of CD34+CD38- cells and of the long term HSC-enriched subpopulation (CD34+CD38-CD45RA-Thy1+) in M-OST CM cultures were respectively 2.7- and 2.8-fold greater than those measured in control cultures (n=2-4). Finally, the impact of M-OST CMs on the expansion of myeloid progenitors was investigated using a colony forming assay; expansion of myeloid progenitors were superior in all M-OST CM cultures (1.6±0.2 fold, n=2). In conclusion, our results demonstrate that M-OST rapidly acquire the expression of growth factors known to promote HSPC expansion. Moreover, the capacity of M-OST CMs to support the expansion of HSPCs appears to be a property shared by M-OST at various stages of maturation. Disclosures No relevant conflicts of interest to declare.

scholarly journals TGF-β Signaling in Stromal Cells Contributes to Myelofibrosis, but Not Niche Disruption, in Myeloproliferative Neoplasms

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1463-1463
Author(s):  
Juo-Chin Yao ◽  
Daniel C. Link
Keyword(s):  
Bone Marrow ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Myeloproliferative Neoplasms ◽  
Extramedullary Hematopoiesis ◽  
Bone Marrow Niche ◽  
Kit Ligand ◽  
Ligand Expression ◽  
The Impact ◽  
Hematopoietic Niche

Abstract Myeloproliferative neoplasms are associated with significant alterations in the bone marrow microenvironment that contribute to disease pathogenesis. The most striking alteration is the development of myelofibrosis, which is characterized by extensive collagen deposition in the bone marrow and is associated with a poor prognosis. Recent evidence suggests that expression of key niche factors, including CXCL12 (stromal derived factor-1, SDF-1) and Kit ligand are reduced in MPNs. This is relevant, since studies by our group and others have shown that deleting these niche factors from stromal cells results in a shift in hematopoiesis from the bone marrow to spleen. Indeed, a prominent feature of MPN is the development of splenomegaly and extramedullary hematopoiesis. There is evidence implicating inflammatory mediators in the development of myelofibrosis. In particular, increased production of TGF-β produced by megakaryocytes and monocytes is found in most patients with MPNs. To assess the role of TGF-β signaling in mesenchymal stromal cells in the bone marrow in the development of myelofibrosis, we generated Osx-Cre; Tgfbr2 f/- mice, in which TGF-β signaling is abrogated in all bone marrow mesenchymal stromal cells (including Lepr + stromal cells), but not endothelial cells or hematopoietic cells. We transplanted MPL W515L transduced hematopoietic stem and progenitor cells (HSPCs) or JAK2 V617F bone marrow into these mice and quantified myelofibrosis using reticulin staining and Collagen 1 and 3 immunostaining. We previously reported that deletion of TGF-β signaling in mesenchymal stromal cells in these mice abrogated the development of myelofibrosis, and we presented evidence that this was mediated by non-canonical JNK-dependent TGF-β signaling. Here, we describe the impact of stromal TGF-β signaling on the bone marrow hematopoietic niche in MPN. MPL W515L transduced HSPCs were transplanted into Osx-Cre; Tgfbr2 f/- mice, and the impact on hematopoietic niche disruption and development of extramedullary hematopoiesis was assessed. In control recipients, transplantation of MPL W515L HSPCs resulted in marked decreases in bone marrow Cxcl12 and Kit ligand expression (Figure 1A-B). Surprisingly, a similar decrease was observed in Osx-Cre; Tgfbr2 f/- recipients. The loss of these key niche factors is predicted to impair hematopoietic niche function in the bone marrow. Consistent with this prediction, total bone marrow cellularity and HSC number were significantly reduced in both control and Osx-Cre; Tgfbr2 f/- recipients (Figure 1C-D). Finally, disruption of the bone marrow niche is often associated with extramedullary hematopoiesis. Indeed, a significant increase in spleen size and spleen HSCs and erythroid progenitors was observed in control recipients (Figure 1E-G). Again, a similar phenotype was observed in Osx-Cre; Tgfbr2 f/- recipients. Collectively, these data show that TGF-β signaling in bone marrow mesenchymal stromal cells is required for the development of myelofibrosis but not hematopoietic niche disruption in MPNs. Thus, these data show for the first time that the signals that induce a fibrogenic program in bone marrow mesenchymal stromal cells are distinct from those that suppress Cxcl12 and Kit ligand expression. Our data show that the fibrogenic program is dependent on non-canonical JNK-dependent TGF-β signaling, while the signals that regulate niche factor expression remain unknown. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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