scholarly journals Impairment of AML Engraftment to the Bone Marrow Niche Following Inhibition of TGF-Beta Signaling

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4372-4372 ◽  
Author(s):  
Ashley Hamilton ◽  
Katie Foster ◽  
Dominique Bonnet
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Microenvironment ◽  
Laminin Receptor ◽  
Cytokine Signaling ◽  
Bone Marrow Niche ◽  
Tgf Beta ◽  
Stromal Compartment ◽  
Β Receptor

Abstract The cell fate of the HSC to either self-renew or differentiate is controlled by a complex interplay between cell-intrinsic and -extrinsic regulatory signals generated by the surrounding bone marrow microenvironment called the HSC niche. A balance exists within the “cross talk” between HSCs and the niche, which allows HSC dormancy, activation and differentiation. Any alterations of this balance may lead to uncontrolled cellular proliferation and ultimately the promotion of leukemia. However, it remains to be determined exactly how the hematopoietic microenvironment contributes to the deregulation of normal hematopoiesis and/or promotes the maintenance of leukemia cells as a “leukemic niche”. To investigate this, we have now performed micro-array analysis of MS5 stromal cells that were co-cultured with a panel of leukemic cell lines and acute myeloid leukemia (AML) patient samples. The most significantly up-regulated pathways as compared to MS5 cells cultured alone involved cytoskeleton remodeling, cell cycle, cell adhesion and development through cytokine signaling. Since transcript and protein levels of number of effectors of the TGF-beta (TGF-β) signaling pathway were up-regulated in the stroma co-cultured with leukemic cells, we next investigated inhibition of this pathway using a specific inhibitor of TGF-β receptor kinase, SB-431542 (10µM). Treatment with the inhibitor significantly reduced the cell number and increased the levels of apoptosis in the AML cells co-cultured on stromal cells, whilst having mininal effect on normal cells. Treatment with SB-431542 (10mg/kg), also significantly reduced the level of AML cell engraftment on treatment in vivo (n=3) (untreated- 68.65±6.95; 56.15±22.85; 84.35±5.75 and SB-treated- 45.5±11.6; 30.5±19.6; 54.1±4.9). In order to inhibit TGF-β signaling more specifically within the stromal compartment, we next used shRNA against TGF-β Receptor II (TGFBR2) in MS5 stromal cells and co-cultured them with AML cells within 3D scaffold models (n=4), which were implanted in vivo. A significant reduction in engraftment was observed as compared to controls (shRNA control- 64.65±32.65; 87.7±7.2; 23.55±4.35; 49.65±33.65 and TGFBR2 knockdown- 20.2±3; 62.95±4.05; 15.7±1.5; 20.385±17.415). The co-culturing of normal cord blood CD34+ or mononuclear cells on the TGFBR2 knockdown stroma had no significant effect both in vitro and in vivo (n=3). To investigate whether TGF-β inhibition had an effect on the interaction of AML cells to the niche, we used intravital microscopy to track the cells live in vivo. HL60 (AML cell line) cells were labeled with 2µM CFSE and pretreated ±SB-431542 (10µM) on stroma, before being sorted and transplanted into immunodeficient mice. Distance to the calvaria was measured at 16 hours and we observed that the SB-431542-treated cells were positioned significantly further away from the bone surface as compared to untreated control (p=0.0001). Since the TGF-β inhibited cells appeared to have impaired ability to adhere to the bone marrow, we next investigated the relationship between extracellular matrix molecules and TGF-β signaling. We saw that stromal cells that were co-cultured with AML cells had a significantly increased expression of laminins A1, A5, B1 and G1. This effect could be recapitulated by treatment of naïve stromal cells with TGF-β2 and 3. We also observed a reciprocal decrease in expression of laminins following both treatment of AML-stromal co-cultures with SB-431542 and within TGFBR2 knockdown stroma. Furthermore, we saw an increase in the laminin receptor, integrin alpha-6 (CD49f), in AML cells treated with TGF-β 1, 2 and 3 and a reciprocal decrease following treatment with SB-431542, thereby, indicating that the abrogation of this signaling axis may be, at least, partially responsible for the impaired engraftment of AML cells to their niche following inhibition of the TGF-β pathway. These data thus highlight the potential for the development of therapies directed at modifying the bone marrow microenvironment. Disclosures No relevant conflicts of interest to declare.

Leukemia-Derived Exosomes Reorganize Bone Marrow Microenvironment In AML

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2455-2455
Author(s):  
Bijender Kumar ◽  
Lihong Weng ◽  
Xiaoman Lewis ◽  
Jodi Murakami ◽  
Xingbin Hu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Leukemia Cell ◽  
Bone Marrow Microenvironment ◽  
Leukemia Cells ◽  
Control Group ◽  
Hematopoietic Progenitors ◽  
Stromal Compartment

Abstract Increasing evidence suggests that leukemia cells take shelter in the bone marrow (BM) microenvironment (niche), where they hide from chemotherapy and continue to divide. As yet, the identity of niche cells and secreted factors that facilitate leukemia cell growth and assist them in evading chemotherapy is unclear. Further, how leukemia cells alter the bone marrow microenvironment is not known yet. In this study, we provide compelling evidences of a novel role of leukemia-derived exosomes in altering the microenvironment constituents by paracrine mechanisms.As proof-of-concept, we analyzed the cytokines mRNA profiles of primary human and mouse stromal cell co-cultured with primary CD34+CD38- cells from AML patients. Stromal cells co-cultured with leukemia showed increased levels of IL-6, IL-1β, VEGFα, TNF and reduced SDF1 mRNA expression. Similar pattern of gene expression changes were observed from stroma cells co-cultured with leukemia-derived exosomes.By using CFSE labeled exosomes, we observed that leukemia-derived exosomes target marrow stromal and endothelial cells both in-vitro and in-vivo directly. In our in vivo AML model, established using xenografted AML cell lines or primary AML patient samples in Rag2-/- γc-/-mice, we observed expansion of LT-HSC and hematopoietic progenitors compartment. The leukemia animals also showed cellular composition changes in the stromal compartment suggesting osteoblast differentiation was blocked. Interestingly, milder but similar changes were observed in mice treated with leukemia-derived exosomes. Exosomes derived from normal human peripheral blood did not induce significant changes in either hematopoietic or stromal compartments in recipient mice. These data indicate that leukemia cells secrete specialized exosomes to modulate the BM microenvironment. Fluidigm dynamic array analysis of BM stromal cells from leukemic mice revealed that the cell adhesion molecules (NCAM1, VCAM1, CD44, OPN & ICAM1) and factors important for angiogenesis (Angpt1, Angpt 2 &VEGF) were all upregulated in leukemia-modified stromal cells whereas genes important for osteoblast (OCN, OSX), chondrocyte (SOX9) development and HSC maintenance (SDF1 and SCF) were down regulated. These results suggest that leukemia cells can remodel the BM microenvironment by changing the stromal cell composition and influencing expression of important molecular regulators. To evaluate the HSC functions in exosomes-treated mice, we used 5-fluorouracil (5-FU) to suppress hematopoiesis and induce myeloablative stress. Leukemia-derived exosome-pretreated mice succumbed to death earlier compared to the control group (p=0.0001) suggesting that HSCs from leukemia-derived exosome-treated mice may have lower stem cell activity than their counterparts from normal mice. Furthermore, more LT-HSC and hematopoietic progenitors from leukemia-derived exosome-pretreated mice were in active cell cycle (p=0.004 and p=0.01 respectively). These findings support our hypothesis that leukemia cells/exosomes directly or indirectly through leukemia-modified niche, altered the HSCs physiological and quiescence properties. Next we analyzed the ability of leukemia-modified niche to support the normal hematopoiesis. We co-cultured freshly sorted normal CD45.2 LT-HSCs (LSK CD150+CD48-Flk2-) with leukemia cells/exosomes pre-treated stroma cells for 48 hours and transplanted the co-cultured HSC into irradiated CD45.1 mice. 18 weeks after transplantation, we observed a significantly decreased engraftment of the HSCs co-cultured with leukemic cells/exosomes stroma compared with the HSCs co-cultured with normal stroma (p=0.003). Finally, leukemia engrafted better and developed more rapidly (p=0.0026) in mice that received leukemia-derived exosomes pre-treatment. These data suggest that changes induced by leukemia-derived exosomes in the BM niche accelerate leukemia progression and decrease their ability to support HSCs. Collectively, our data demonstrate that the leukemia cells manipulate the bone marrow microenvironment, partly through leukemia-derived exosomes, to suppress the normal hematopoiesis and facilitate growth of the leukemic progeny. Disclosures: No relevant conflicts of interest to declare.

scholarly journals In Vivo Labeling by CD73 Marks Multipotent Stromal Cells and Highlights Endothelial Heterogeneity in the Bone Marrow Niche

2018 ◽  
Vol 22 (2) ◽  
pp. 262-276.e7 ◽  
Author(s):  
Martin Breitbach ◽  
Kenichi Kimura ◽  
Tiago C. Luis ◽  
Christopher J. Fuegemann ◽  
Petter S. Woll ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Niche ◽  
Multipotent Stromal Cells ◽  
In Vivo Labeling ◽  
Endothelial Heterogeneity

Human Extramedullary Bone and Bone Marrow in Mice: First In Vivo Model of a Genetically Controlled Hematopoietic Environment

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1323-1323
Author(s):  
Ye Chen ◽  
Rodrigo O Jacamo ◽  
Nicole A. Hofmann ◽  
Yue-xi Shi ◽  
Rui-yu Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Microenvironment ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Leukemic Cells ◽  
Artificial Bones ◽  
Hematoxylin And Eosin ◽  
Bone Structures

Abstract Abstract 1323 The importance of the tumor microenvironment for cancer development, progression and resistance to treatment has recently been recognized. Our group was first to report the contribution of bone marrow (BM) derived mesenchymal stromal cells (MSCs) for tumor development and metastasis. BM is also the dynamic microenvironment (niche) for normal and malignant hematopoietic stem cells (HSC) with high local concentrations of growth factors, chemokines and cytokines. The maintenance of HSCs quiescence and normal hematopoiesis require complex bidirectional interactions between the BM niches and HSCs. Accumulating evidence has shown that the BM microenvironment also plays a pivotal role in the pathophysiology and propagation of leukemia. Leukemia cells undergo spontaneous apoptosis once they are removed from the in vivo microenvironment and placed in suspension cultures without supportive stroma. The understanding of the interactions between leukemic cells and their BM niche is also critically important for leukemia therapy. We here describe a novel artificial bone and bone marrow model mimicking the human hematopoietic microenvironment by using human BM derived MSCs and endothelial colony-forming cells (ECFCs). MSCs and ECFCs were isolated from heparinized human bone marrow or peripheral blood through an initial adhesion step, grown in specific media and then subcutaneously injected into the flanks of the NOD/SCID/IL-2r-gammanull mice, where they developed into bone-like tissues with high osteoblast activity after 10 weeks (Figure 1). Histochemical stains confirmed the bone structures and also showed that these artificial bones contained typical bone marrow cavities constituting a robust hematopoietic environment. In vivo imaging with Osteosense confirmed the presence of hydroxylapatite, and luciferase imaging of firefly luciferase labeled human leukemic cells demonstrated the engraftment of MOLM13/Luc/GFP leukemic cells in the extramedullary BM sites. The extramedullary BM was markedly hypoxic, as shown by Pimonidazole staining, another critical feature of the BM microenvironment. Factors critical for MSC to support the normal and leukemic hematopoiesis are largely unknown and cannot be studied since human MSC do not engraft reliably in xenograft models. We therefore investigated the possibility of genetically modifying MSC in this system and found a significant reduction (50 ± 6%, p<0.001) in MOLM13 cell engraftment in extramedullary BM generated with HIF1-alpha knockdown MSCs (1449 ± 194 cells/mm2), compared to vector controls (3037 ± 496 cells/mm2). This finding indicates that the HIF1-alpha expression in stromal cells is a critical component for the engraftment of leukemic cells in the physiologically hypoxic BM microenvironment. These results, for the first time, establish an in vivo bone and bone marrow model with a genetically controlled human microenvironment.Figure 1Establishment a human bone marrow microenvironment in NOD/SCID/IL-2r-gammanullmice. Representative hematoxylin and eosin (H&E) staining (shown at low magnification) shows an overview of the extramedullary bones with the typical bone structures. Scale bar: 1 mm.Figure 1. Establishment a human bone marrow microenvironment in NOD/SCID/IL-2r-gammanull mice. Representative hematoxylin and eosin (H&E) staining (shown at low magnification) shows an overview of the extramedullary bones with the typical bone structures. Scale bar: 1 mm. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment

2017 ◽  
Author(s):  
Christine Lam ◽  
Megan Murnane ◽  
Hui Liu ◽  
Geoffrey A. Smith ◽  
Sandy Wong ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Plasma Cells ◽  
Single Agent ◽  
Drug Repurposing ◽  
Myeloma Cell ◽  
Bone Marrow Microenvironment ◽  
Growth Promoting

AbstractThe myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Interleukin-6 (IL-6) and downstream JAK/STAT signaling are thought to be central components of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor FDA-approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Here, we validated bothin vitro, in stromal-responsive human myeloma cell lines, andin vivo, in orthotopic disseminated murine xenograft models of myeloma, that tofacitinib showed both single-agent and combination therapeutic efficacy in myeloma models. Surprisingly, we found that ruxolitinib, an FDA-approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not enhance ruxolitinib effects. RNA-seq and unbiased phosphoproteomics revealed that marrow stromal cells stimulate a JAK/STAT-mediated proliferative program in myeloma plasma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib specifically reverses the growth-promoting effects of the tumor microenvironment through blocking an IL-6-mediated signaling axis. As tofacitinib is already FDA-approved, these results can be rapidly translated into potential clinical benefits for myeloma patients.

Bone Marrow Mesenchymal Stromal Cells Transfer Their Mitochondria to Acute Myeloid Leukaemia Blasts to Support Their Proliferation and Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 772-772 ◽  
Author(s):  
Christopher Marlein ◽  
Lyubov Zaitseva ◽  
Rachel E Piddock ◽  
Stephen Robinson ◽  
Dylan R Edwards ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Line ◽  
Stromal Cells ◽  
Mitochondrial Protein ◽  
Bone Marrow Microenvironment ◽  
Mitochondrial Mass ◽  
Mitochondrial Transfer ◽  
Acute Myeloid

Abstract Background Survival of acute myeloid leukaemia (AML) blasts is established to be heavily dependent on the bone marrow microenvironment, where bone marrow mesenchymal stromal cells (BM-MSCs) are an important cell type. Contrary to the Warburg hypothesis, AML blasts rely on oxidative phosphorylation for survival and have increased mitochondrial levels compared to normal CD34+ progenitors. Current research is being directed at the biology behind how the bone marrow microenvironment supports the proliferation of the disease. With the knowledge that AML blasts have an increased mitochondrial mass and that BM-MSCs have the ability to be mitochondrial donors, we examined the BM-MSC AML blast interaction to determine if the increased mitochondrial mass was a result of inter-cellular mitochondrial transfer. Methods Primary AML blasts were obtained from patient bone marrow. Primary AML and normal BM-MSCs were isolated from patients bone marrow, with informed consent and under approval from the UK National Research Ethics Service (LRCEref07/H0310/146), using adherence. BM-MSCs were characterised using flow cytometry for expression of CD90+, CD73+, CD105+ and CD45-. Mitochondrial transfer was assessed in vitro using qPCR and MitoTracker staining based methods. A P0 OCI-AML3 cell line was created using a 40-day incubation with ethidium bromide, pyruvate and uridine. In vivo experiments using an NSG primary AML xenograft model were also carried out (in accordance with University of East Anglia ethics review board). For mechanistic determination, BM-MSCs with a mCherry mitochondrial labelled protein were created using a lentivirus. Levels of mitochondrial transfer were assessed by mCherry mitochondrial protein acquisition in the AML during co-culture with the BM-MSCs. Results We report that BM-MSCs support AML blast survival via the inter-cellular transfer of mitochondria from 'benign' to malignant cells. To examine this transfer we used primary AML blasts and BM-MSCs derived from patient bone marrow, along with AML cell lines. We found in vitro that primary AML blasts increase their mitochondrial mass, respiratory capacity and ATP production after co-culture with primary BM-MSCs. A P0 OCI-AML3 cell line, with mutated mitochondrial DNA (mtDNA), was generated using ethidium bromide treatment allowing mitochondrial transfer to be specifically analysed. mtDNA was restored in this cell line after co-culture with primary BM-MSCs. Further to this mouse mtDNA was detected in the P0 OCI-AML3 cells after co-culture with the mouse BM-MSC cell line (M2-10B4). Moreover, mitochondrial transfer was directly observed between primary BM-MSCs and primary AML blasts, visualised by the acquisition of a mCherry labelled mitochondrial protein. This transfer of mitochondria was one directional. Moreover, a reduction of mitochondrial transfer was observed in AML blasts upon the addition of cytochalasin to the co-culture, highlighting that mitochondrial transfer is at least in part facilitated through tunnelling nanotubes (TNTs). Finally, mitochondrial transfer was confirmed in vivo whereby murine mitochondria were transferred to human AML in a mouse xenografts model. Conclusion Here we show that the bone marrow microenvironment supports the AML blasts by donating mitochondria, which in turn enhances the oxidative phosphorylation and growth capacity of the blasts. Targeting the microenvironment is predicted to provide novel therapeutic approaches for the treatment of cancer. Disclosures Rushworth: Infinity Pharmaceuticals: Research Funding.

scholarly journals Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML

Blood ◽  
2009 ◽  
Vol 113 (24) ◽  
pp. 6215-6224 ◽  
Author(s):  
Zhihong Zeng ◽  
Yue Xi Shi ◽  
Ismael J. Samudio ◽  
Rui-Yu Wang ◽  
Xiaoyang Ling ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Fetal Liver ◽  
Bone Marrow Microenvironment ◽  
Leukemic Cells ◽  
In Vivo Studies ◽  
Protective Effects ◽  
Cxcr4 Signaling ◽  
Induced Apoptosis

Abstract SDF-1α/CXCR4 signaling plays a key role in leukemia/bone marrow microenvironment interactions. We previously reported that bone marrow–derived stromal cells inhibit chemotherapy-induced apoptosis in acute myeloid leukemia (AML). Here we demonstrate that the CXCR4 inhibitor AMD3465 antagonized stromal-derived factor 1α (SDF-1α)–induced and stroma-induced chemotaxis and inhibited SDF-1α–induced activation of prosurvival signaling pathways in leukemic cells. Further, CXCR4 inhibition partially abrogated the protective effects of stromal cells on chemotherapy-induced apoptosis in AML cells. Fetal liver tyrosine kinase-3 (FLT3) gene mutations activate CXCR4 signaling, and coculture with stromal cells significantly diminished antileukemia effects of FLT3 inhibitors in cells with mutated FLT3. Notably, CXCR4 inhibition increased the sensitivity of FLT3-mutated leukemic cells to the apoptogenic effects of the FLT3 inhibitor sorafenib. In vivo studies demonstrated that AMD3465, alone or in combination with granulocyte colony-stimulating factor, induced mobilization of AML cells and progenitor cells into circulation and enhanced antileukemic effects of chemotherapy and sorafenib, resulting in markedly reduced leukemia burden and prolonged survival of the animals. These findings indicate that SDF-1α/CXCR4 interactions contribute to the resistance of leukemic cells to signal transduction inhibitor– and chemotherapy-induced apoptosis in systems mimicking the physiologic microenvironment. Disruption of these interactions with CXCR4 inhibitors represents a novel strategy of sensitizing leukemic cells by targeting their protective bone marrow microenvironment.

Disruption of Leukemia/Stroma Cell Interactions by CXCR4 Antagonist CTCE-9908 Enhances Chemotherapy-Induced Apoptosis in AML

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2415-2415
Author(s):  
Hongbo Lu ◽  
Zhihong Zeng ◽  
Yuexi Shi ◽  
Sergej Konoplev ◽  
Donald Wong ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Leukemia Cell ◽  
Bone Marrow Microenvironment ◽  
Cell Interactions ◽  
Leukemic Cells ◽  
Dependent Manner ◽  
Induced Apoptosis ◽  
Dose Dependent

Abstract The chemokine receptor CXCR4 is critically involved in the migration of hematopoietic cells towards the stromal derived factor (SDF-1α)-producing bone marrow microenvironment. We and others have previously demonstrated that stroma/leukemia interactions mediate protection of leukemic cells from chemotherapy-induced apoptosis (Konopleva, Leukemia 2002). Using a peptide analog of SDF-1α designated CTCE-9908, we tested the hypothesis that CXCR4 inhibition interferes with stromal/leukemia cell interactions resulting in increased sensitivity to chemotherapy. Our results showed that CTCE-9908 significantly inhibits SDF-1α-induced migration of U937 (43% inhibition) and OCI-AML3 cells (40% inhibition) in a dose-dependent manner. In three of the four primary AML samples which expressed CXCR4 on cell surface and migrated in response to SDF-1α, 50 μg/ml CTCE-9908 reduced SDF-1α-induced migration of leukemic blasts (60%, 19% and 50% inhibition respectively). In in vitro co-culture systems, stromal cells significantly protected OCI-AML3 cells from chemotherapy induced apoptosis [no MS-5, 75.2±5.2% annexinV(+); with MS-5, 59±1.1% annexinV(+)]. Western blot analysis revealed that CTCE-9908 inhibits Akt and Erk phosphorylation in a dose-dependent manner in the OCI-AML3 cell line stimulated by SDF-1α. Blockade of CXCR4 expression with CTCE-9908 markedly abrogated the protective effects of stromal cells on OCI-AML3 [Ara-C, 59±1.1% annexinV(+); Ara-C + CTCE-9908, 76.9±1.35 annexinV(+)]. Most importantly, it decreased stroma-mediated protection from AraC-induced apoptosis in four out of five primary AML samples with surface expression of functional CXCR4 (mean increase, 25.1±9.3% compared to chemotherapy alone). In vivo, subcutaneous administration of 1.25mg CTCE-9908 induced mobilization of leukemic cells from primary AML patient transplanted into NOD/Scid-IL2Rγ-KO mice (from 15% to 27% circulating leukemic cells 1 hour post CTCE-9908 injection). Taken together, our data suggest that SDF-1α/CXCR4 interactions contribute to the resistance of leukemic cells to chemotherapy-induced apoptosis via retention of leukemic cells in the bone marrow microenvironment niches. Disruption of these interactions by the potent CXCR4 inhibitor CTCE-9908 represents a novel strategy for targeting leukemia cell/bone marrow microenvironment interaction. Based on these observations, in vivo experiments are ongoing to characterize the efficacy of chemotherapy combined with CTCE-9908.

scholarly journals Experimental Type 2 Diabetes Differently Impacts on the Select Functions of Bone Marrow-Derived Multipotent Stromal Cells

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 268
Author(s):  
Jonathan Ribot ◽  
Cyprien Denoeud ◽  
Guilhem Frescaline ◽  
Rebecca Landon ◽  
Hervé Petite ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Adipogenic Differentiation ◽  
Therapeutic Modality ◽  
Multipotent Stromal Cells ◽  
Cell Therapies

Bone marrow-derived multipotent stromal cells (BMMSCs) represent an attractive therapeutic modality for cell therapy in type 2 diabetes mellitus (T2DM)-associated complications. T2DM changes the bone marrow environment; however, its effects on BMMSC properties remain unclear. The present study aimed at investigating select functions and differentiation of BMMSCs harvested from the T2DM microenvironment as potential candidates for regenerative medicine. BMMSCs were obtained from Zucker diabetic fatty (ZDF; an obese-T2DM model) rats and their lean littermates (ZL; controls), and cultured under normoglycemic conditions. The BMMSCs derived from ZDF animals were fewer in number, with limited clonogenicity (by 2-fold), adhesion (by 2.9-fold), proliferation (by 50%), migration capability (by 25%), and increased apoptosis rate (by 2.5-fold) compared to their ZL counterparts. Compared to the cultured ZL-BMMSCs, the ZDF-BMMSCs exhibited (i) enhanced adipogenic differentiation (increased number of lipid droplets by 2-fold; upregulation of the Pparg, AdipoQ, and Fabp genes), possibly due to having been primed to undergo such differentiation in vivo prior to cell isolation, and (ii) different angiogenesis-related gene expression in vitro and decreased proangiogenic potential after transplantation in nude mice. These results provided evidence that the T2DM environment impairs BMMSC expansion and select functions pertinent to their efficacy when used in autologous cell therapies.

scholarly journals Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 68
Author(s):  
Fulvio Massaro ◽  
Florent Corrillon ◽  
Basile Stamatopoulos ◽  
Nathalie Meuleman ◽  
Laurence Lagneaux ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Cell Communication ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Wide Range ◽  
Major Player

Aging of bone marrow is a complex process that is involved in the development of many diseases, including hematologic cancers. The results obtained in this field of research, year after year, underline the important role of cross-talk between hematopoietic stem cells and their close environment. In bone marrow, mesenchymal stromal cells (MSCs) are a major player in cell-to-cell communication, presenting a wide range of functionalities, sometimes opposite, depending on the environmental conditions. Although these cells are actively studied for their therapeutic properties, their role in tumor progression remains unclear. One of the reasons for this is that the aging of MSCs has a direct impact on their behavior and on hematopoiesis. In addition, tumor progression is accompanied by dynamic remodeling of the bone marrow niche that may interfere with MSC functions. The present review presents the main features of MSC senescence in bone marrow and their implications in hematologic cancer progression.

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