Human Placental Derived Mesenchymal Stromal Cells (MSC) Grown in 3D-Culture (PLX-I), Promotes Engraftment of Human Umbilical Cord Blood (hUCB) Derived CD34+ Cells in NOD/SCID Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1416-1416 ◽  
Author(s):  
Ora Burger ◽  
Galit F. Ashtamker ◽  
Noam Bercovich ◽  
Marina Rusanovsky ◽  
Lena Pinzur ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
3D Culture ◽  
Scid Mice ◽  
Mice Model ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Cell Engraftment ◽  
Cd34 Cells ◽  
I Cells

Abstract The use of UCB for transplantation in adults is limited due to the low cell number in each unit. Engraftment rates are lower and the time for neutrophil and platelet recovery is longer following CBT compared to bone marrow (BM) transplants. Co-transplantation of human hematopoietic stem/progenitor cells (HSC) with mesenchymal stromal cells in an irradiated NOD/SCID mice model has been demonstrated to promote HSC engraftment. Using PluriX technology, we expanded human placental derived MSC on 3D-carriers in a bioreactor (PLX-I) and evaluated its potential to promote UCB engraftment in the NOD/SCID mice model. Flow cytometer analysis detected high rates of expression of CD105, CD73, CD90 and CD29 and lacked expression of CD45, CD34 and CD19 surface markers in the PLX-I cells. PLX-I cells were capable of differentiation into bone, adipose tissue and cartilage under specific inductive conditions. Additionally, they possess both immune privileged and immune suppressive characteristics in a mixed lymphocyte reaction (MLR) assay. In this study 60 – 100x103 hUCB derived CD34+ cells were injected into the tail vein of 7–8 week old NOD/SCID mice along with 0.5x106 PLX-I cells. Human cell engraftment was tested in both sublethally irradiated (350 rad) and chemotherapy (50 mg/kg busulfan) treated NOD/SCID mice. Following 5–6 weeks, mice BM FACS analysis showed a significant increase in % hCD45+ rate in mice transplanted with PLX-I cells compared to mice transplanted with CD34+ cells alone: 13.6 vs. 31.7, p=0.01, (n=6) in the irradiation setting and 28.8 vs 6.3, p<0.05 (n=7) in the chemotherapy setting. These preclinical results demonstrate the potential of human placental-derived MSCs, grown as a 3D culture (PLX-I), to promote hUCB CD34+ cell engraftment in BM. Co-transplantation of PLX-I may be considered for improving the delayed engraftment using CB as the source of HSC.

3D Grown Human Placental-Derived Mesenchymal Stromal Cells (PLX-I) Support and Potentiate the Engraftment of Human Cord Blood Unfractionated (UFCBC) and Fractionated CD34+ Cells (hCD34+) in Irradiated NOD/SCID Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4104-4104
Author(s):  
Ora Burger ◽  
Osnat M. Jacov ◽  
Nirit D. Carmi ◽  
Galit F. Ashtamker ◽  
Lena Pinzur ◽  
...  
Keyword(s):  
Cord Blood ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Clinical Setting ◽  
Scid Mice ◽  
Human Umbilical Cord ◽  
Mice Model ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Cd34 Cells

Abstract The use of human umbilical cord blood (hUCB) for transplantation (CBT) in adults is limited due to the low cell number in each unit. Engraftment rates are lower and the time to neutrophils and platelet recovery is longer following CBT compared to bone marrow (BM) transplantation (28 vs 14 days, respectively). Co-transplantation of human hematopoietic stem/progenitor cells (hHSC) with mesenchymal stromal cells in an irradiated NOD/SCID mice model has been demonstrated to promote HSC engraftment. In a typical clinical setting of CBT, unfractionated cord blood cells (UFCBC) are usually used. On the other hand, in the irradiated NOD/SCID mice model, the CD34+ enriched fraction is usually used. Therfore, performing pre-clinical studies using UFCBC would better reflect the outcome in the clinical setting. Using PluriX technology, we expanded human placental derived mesenchymal stromal cells on 3D carriers in a bioreactor (PLX-I) and evaluated their potential to promote the engraftment of UFCBC or hUCB derived fractionated CD34+ cells (hCD34+) in NOD/SCID mice. UFCBC (107) or hCD34+ (5×104) were injected into the tail vein of 7–8 week old NOD/SCID mice along with 0.5×106 or 1×106 PLX-I cells. Following 5–6 weeks, FACS analysis of % human CD45+ cells in mice BM demonstrated that in the PLX-I untreated mice, the 107 UFCBC engrafted in a lower rate compare to 5*104 hCD34+ (6.28% vs. 14.43% respectively, n=10). Furthermore, in both settings, hCD34+ and UFCBC, the addition of PLX-I enhanced the hHSC engraftment 1.7 and 2 fold respectively compared to PLX-I untreated mice (24.13% vs. 14.43% in hCD34+ setting and 12.85% vs. 6.28% in UFCBC setting, n=10). We conclude that UFCBC can be used for hHSC engraftment in NOD/SCID mice model and co-transplantation of these cells with PLX-I may serve as a promising approach for the improvement of the hitherto delayed engraftment following cord blood transplantation.

Prospective Isolation and Functional Characterization of Human Bone Marrow-Derived Hematopoietic Stem Cell-Supportive Mesenchymal Stromal Cells.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3852-3852
Author(s):  
Yoshikazu Matsuoka ◽  
Yutaka Sasaki ◽  
Masaya Takahashi ◽  
Ryusuke Nakatsuka ◽  
Yasushi Uemura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Scid Mice ◽  
Hematopoietic Stem ◽  
Human Cd34 ◽  
Cd34 Cells

Abstract Abstract 3852 (Background) The identification of human CD34-negative (CD34−) SCID-repopulating cells (SRCs) provide a new concept for the hierarchy in the human HSC compartment (Blood 101:2924, 2003). Recently, we succeeded to highly purify these CD34-SRCs using 18 lineage specific antibodies (Blood 114:336, 2009). It has been suggested that human hematopoietic stem cell (HSC)-supportive microenvironment exist in the bone marrow (BM), which play a pivotal role in the maintenance of self-renewal capacity and dormancy of primitive HSCs. It was reported that osteoblasts and vascular endothelial cells played an important role to organize HSC niches. However, whether mesenchymal stromal cells (MSCs) contribute to organize HSC niches or not is not clearly understood, because MSCs are heterogeneous population. Therefore, it is important to clarify their origin and functional characteristics. (Objectives) The aim of this study was to prospectively isolate/identify human BM-derived MSCs and investigate their functional characteristics including HSC-supportive abilities. (Results) First, human BM-derived Lin−CD45− cells were subdivided into 4 fractions according to their expression levels of CD271 and SSEA-4 by FACS. We succeeded to isolate 3 MSC lines from these 4 fractions, including CD271+/&minus;SSEA-4+/&minus; cells. Approximately 1 out of 6 CD271+SSEA-4+ (DP) cells could form MSC-derived colony. These DP cells-derived MSCs could differentiate into osteoblasts and chondrocytes, but could not differentiate into adipocytes. In contrast, CD271+SSEA-4− cells and CD271−SSEA-4− cells-derived MSCs could differentiate into three lineages. Then, we assessed CD34− SRC-supportive activity of these 3 MSC lines. First, certain numbers of 18Lin−CD34− cells were cocultured with 3 MSC lines for 1 week, respectively. Next recovered cells were transplanted into NOD/SCID mice by intra-bone marrow injection (IBMI) to investigate SCID-repopulating cell (SRC) activity. After 8 weeks, the highest CD45+ human cell engraftments (0.1 % to 32.4 %, median 8.6 %) were observed in mice received 18Lin−CD34− cells cocultued with DP cells-derived MSCs. As recently reported (Cell Stem Cell 1:635,2007), Lin−CD34+CD38−CD45RA−CD90+ cells contained most primitive human CD34+CD38− SRCs. Very interestingly, these Lin−CD34+CD38−CD45RA−CD90+ cells were generated from the above mentioned cocultures. In order to evaluate SRC activity of these Lin−CD34+CD38−CD45RA−CD90+ cells generated from 18Lin−CD34− cells in vitro, Lin−CD34+CD38−CD45RA−CD90+/&minus; cells were sorted by FACS and then transplanted into NOD/SCID mice by IBMI. Eight weeks after transplantation, 8 out of 16 mice received Lin−CD34+CD38−CD45RA−CD90+ cells (400 to 3000 cells/mouse) were repopulated with human cells. In contrast, only 2 out of 16 mice received Lin−CD34+CD38− CD45RA−CD90− cells (1500 to 7000 cells/mouse) were repopulated. These results demonstrated that human CB-derived 18Lin−CD34− cells could generate very primitive CD34+CD38− SRCs in vitro. (Conclusion) These findings elucidate that human BM-derived DP cell-derived MSCs can support very primitive human CB-derived CD34− SRCs in vitro and suggest that these CD34− SRCs seem to be more immature than CD34+CD38− SRCs. These results provide a new concept of hierarchy in the human primitive HSC compartment. Disclosures: No relevant conflicts of interest to declare.

Cord blood CD34+ cells expanded on Wharton's jelly multipotent mesenchymal stromal cells improve the hematopoietic engraftment in NOD/SCID mice

2014 ◽  
Vol 93 (5) ◽  
pp. 384-391 ◽  
Author(s):  
Luisa Milazzo ◽  
Francesca Vulcano ◽  
Alessandra Barca ◽  
Giampiero Macioce ◽  
Emanuela Paldino ◽  
...  
Keyword(s):  
Cord Blood ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Multipotent Mesenchymal Stromal Cells ◽  
Scid Mice ◽  
Wharton’S Jelly ◽  
Wharton's Jelly ◽  
Cd34 Cells ◽  
Cord Blood Cd34

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 Hematopoietic Stem and Progenitor Cell Expansion in Contact with Mesenchymal Stromal Cells in a Hanging Drop Model Uncovers Disadvantages of 3D Culture

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Olga Schmal ◽  
Jan Seifert ◽  
Tilman E. Schäffer ◽  
Christina B. Walter ◽  
Wilhelm K. Aicher ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Ex Vivo ◽  
Three Dimensional ◽  
3D Culture ◽  
Hanging Drop ◽  
Mixed Cell ◽  
Hematopoietic Stem ◽  
Extracellular Matrix Components ◽  
Stem And Progenitor Cells

Efficientex vivoexpansion of hematopoietic stem cells with a concomitant preservation of stemness and self-renewal potential is still an unresolved ambition. Increased numbers of methods approaching this issue using three-dimensional (3D) cultures were reported. Here, we describe a simplified 3D hanging drop model for the coculture of cord blood-derived CD34+hematopoietic stem and progenitor cells (HSPCs) with bone marrow-derived mesenchymal stromal cells (MSCs). When seeded as a mixed cell suspension, MSCs segregated into tight spheroids. Despite the high expression of niche-specific extracellular matrix components by spheroid-forming MSCs, HSPCs did not migrate into the spheroids in the initial phase of coculture, indicating strong homotypic interactions of MSCs. After one week, however, HSPC attachment increased considerably, leading to spheroid collapse as demonstrated by electron microscopy and immunofluorescence staining. In terms of HSPC proliferation, the conventional 2D coculture system was superior to the hanging drop model. Furthermore, expansion of primitive hematopoietic progenitors was more favored in 2D than in 3D, as analyzed in colony-forming assays. Conclusively, our data demonstrate that MSCs, when arranged with a spread (monolayer) shape, exhibit better HSPC supportive qualities than spheroid-forming MSCs. Therefore, 3D systems are not necessarily superior to traditional 2D culture in this regard.

scholarly journals Irradiated mesenchymal stromal cells induce genetic instability in human CD34+ cells

2020 ◽  
Author(s):  
Vanessa Kohl ◽  
Oliver Drews ◽  
Victor Costina ◽  
Miriam Bierbaum ◽  
Ahmed Jawhar ◽  
...  
Keyword(s):  
Conditioned Medium ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Genetic Instability ◽  
Extracellular Medium ◽  
Hematopoietic Stem ◽  
Human Cd34 ◽  
Cd34 Cells ◽  
Stem And Progenitor Cells ◽  
Radiation Induced

AbstractRadiation-induced bystander effects (RIBE) in human hematopoietic stem and progenitor cells may initiate myeloid neoplasms (MN). Here, the occurrence of RIBE caused by genotoxic signaling from irradiated human mesenchymal stromal cells (MSC) on human bone marrow CD34+ cells was investigated. For this purpose, healthy MSC were irradiated in order to generate conditioned medium containing potential genotoxic signaling factors. Afterwards, healthy CD34+ cells from the same donors were grown in conditioned medium and RIBE were analyzed. Increased DNA damage and chromosomal instability were detected in CD34+ cells grown in MSC conditioned medium when compared to CD34+ cells grown in control medium. Furthermore, reactive oxygen species and distinct proteome alterations, e.g., heat-shock protein GRP78, that might be secreted into the extracellular medium, were identified as potential RIBE mediators. In summary, our data provide evidence that irradiated MSC induce genetic instability in human CD34+ cells potentially resulting in the initiation of MN. Furthermore, the identification of key bystander signals, such as GRP78, may lay the framework for the development of next-generation anti-leukemic drugs.

Interaction with Human Stromal Cells Enhances CXCR4 Expression and Engraftment of Cord Blood Lin-CD34-Cells Via Wnt Signaling.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2325-2325
Author(s):  
Masayoshi Kobune ◽  
Kazuyuki Murase ◽  
Satoshi Iyama ◽  
Tsutomu Sato ◽  
Shohei Kikuchi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Wnt Signaling ◽  
Cord Blood ◽  
Stromal Cells ◽  
Cxcr4 Expression ◽  
Scid Mice ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Human Stromal Cells

Abstract Ex vivo manipulation of hematopoietic stem/progenitor cells has been performed in preclinical and clinical settings for expansion of hematopoietic stem cells (HSCs) and enhancement of HSC engraftment. Because the absolute HSC dose in a cord blood (CB) unit is a limiting factor for its use as a graft for adult transplant recipients. Transplantation of hematopoietic stem cells (HSCs) is usually accomplished through intravenous injection, a complex process that requires recognition of bone marrow vasculature and migration to a supportive microenvironment. Hence, some populations of HSCs, including cord blood (CB) Lin-CD34-stem cells, do not engraft well in bone marrow (BM) of NOD/SCID mice. In this study, we examined the effect of human stromal interactions on the properties of CB Lin-CD34-cells. CD34 and CXCR4 expression on fresh CB Lin-CD34-cells and CB Lin-CD34-cells co-cultured with human stromal cells were analyzed. Homing activity and engraftment of these cells were assessed using NOD/SCID mice. Co-culture with human stromal cells induced expression of CD34 and CXCR4 on CB Lin-CD34-cells. Furthermore, these cells acquired homing activity and engrafted in the BM of primary and secondary recipients of NOD/SCID mice after intravenous injection. In an attempt to identify the stromal CXCR4-inducing factor, we conducted comparative experiments using stroma-free, contact culture or non-contact culture. As a result, CXCR4 expression on CB Lin-CD34-cells was induced even in the non-contact culture condition but not stroma-free condition, suggesting that this CXCR4-inducing factor is soluble. Because the function of hematopoietic stem/progenitor cells was modulated by several hematopoietic growth factors, angiogenic factors and morphogens, we next screened for soluble CXCR4 inducing factors using blocking antibodies for hedgehog protein, VEGF receptor (anti-KDR) and angiopoietin-1 receptor (anti-Tie2), BMP inhibitor (noggin), pan Wnt inhibitor (sFRP-1), Wnt/β-catenin signaling inhibitor (DKK1) and Wnt/RhoA signaling inhibitor. We found that DKK1 significantly reduced the expression of CXCR4. This indicated that CXCR4 could be regulated by the Wnt signaling pathway. Subsequently, we analyzed the expression of Wnt family members in human stromal cells by RT-PCR. High expression of Wnt1, Wnt2B, Wnt5A and Wnt11 were observed in human stromal cells. Thus, these Wnts may contribute to the induction of CXCR4 expression on CB Lin-CD34-CXCR4-cells. These findings may be useful for understanding the role of stromal cells in homing and engraftment of HSCs and may provide a new strategy to utilize CB and human stromal cells for HSC transplantation.

scholarly journals Genotoxic Bystander Signals from Irradiated Human Mesenchymal Stromal Cells Mainly Localize in the 10–100 kDa Fraction of Conditioned Medium

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 827
Author(s):  
Vanessa Kohl ◽  
Alice Fabarius ◽  
Oliver Drews ◽  
Miriam Bierbaum ◽  
Ahmed Jawhar ◽  
...  
Keyword(s):  
Conditioned Medium ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Heat Inactivation ◽  
Control Medium ◽  
Sample Mean ◽  
Hematopoietic Stem ◽  
Human Mesenchymal Stromal Cells ◽  
Γh2ax Foci ◽  
Cd34 Cells

Genotoxic bystander signals released from irradiated human mesenchymal stromal cells (MSC) may induce radiation-induced bystander effects (RIBEs) in human hematopoietic stem and progenitor cells (HSPC), potentially causing leukemic transformation. Although the source of bystander signals is evident, the identification and characterization of these signals is challenging. Here, RIBEs were analyzed in human CD34+ cells cultured in distinct molecular size fractions of medium, conditioned by 2 Gy irradiated human MSC. Specifically, γH2AX foci (as a marker of DNA double-strand breaks) and chromosomal instability were evaluated in CD34+ cells grown in approximate (I) < 10 kDa, (II) 10–100 kDa and (III) > 100 kDa fractions of MSC conditioned medium and un-/fractionated control medium, respectively. Hitherto, significantly increased numbers of γH2AX foci (p = 0.0286) and aberrant metaphases (p = 0.0022) were detected in CD34+ cells grown in the (II) 10–100 kDa fraction (0.67 ± 0.10 γH2AX foci per CD34+ cell ∨ 3.8 ± 0.3 aberrant metaphases per CD34+ cell sample; mean ± SEM) when compared to (I) < 10 kDa (0.19 ± 0.01 ∨ 0.3 ± 0.2) or (III) > 100 kDa fractions (0.23 ± 0.04 ∨ 0.4 ± 0.4) or un-/fractionated control medium (0.12 ± 0.01 ∨ 0.1 ± 0.1). Furthermore, RIBEs disappeared after heat inactivation of medium at 75 °C. Taken together, our data suggest that RIBEs are mainly mediated by the heat-sensitive (II) 10–100 kDa fraction of MSC conditioned medium. We postulate proteins as RIBE mediators and in-depth proteome analyses to identify key bystander signals, which define targets for the development of next-generation anti-leukemic drugs.

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