Extracellular Vesicles Derived From Adult and Fetal Bone Marrow Mesenchymal Stromal Cells Differentially Promote ex vivo Expansion of Hematopoietic Stem and Progenitor Cells
Recently, we and others have illustrated that extracellular vesicles (EVs) have the potential to support hematopoietic stem and progenitor cell (HSPC) expansion; however, the mechanism and processes responsible for the intercellular communication by EVs are still unknown. In the current study, we investigate whether primary human bone marrow derived mesenchymal stromal cells (BMSC) EVs isolated from two different origins, fetal (fEV) and adult (aEV) tissue, can increase the relative low number of HSPCs found in umbilical cord blood (UCB) and which EV-derived components are responsible for ex vivo HSPC expansion. Interestingly, aEVs and to a lesser extent fEVs, showed supportive ex vivo expansion capacity of UCB-HSPCs. Taking advantage of the two BMSC sources with different supportive effects, we analyzed the EV cargo and investigated how gene expression is modulated in HSPCs after incubation with aEVs and fEVs. Proteomics analyses of the protein cargo composition of the supportive aEV vs. the less-supportive fEV identified 90% of the Top100 exosome proteins present in the ExoCarta database. Gene Ontology (GO) analyses illustrated that the proteins overrepresented in aEVs were annotated to oxidation-reduction process, mitochondrial ATP synthesis coupled proton transport, or protein folding. In contrast, the proteins overrepresented in fEVs were annotated to extracellular matrix organization positive regulation of cell migration or transforming growth factor beta receptor (TGFBR) signaling pathway. Small RNA sequencing identified different molecular signatures between aEVs and fEVs. Interestingly, the microRNA cluster miR-99b/let-7e/miR-125a, previously identified to increase the number of HSPCs by targeting multiple pro-apoptotic genes, was highly and significantly enriched in aEVs. Although we identified significant differences in the supportive effects of aEVs and fEVs, RNAseq analyses of the 24 h treated HSPCs indicated that a limited set of genes was differentially regulated when compared to cells that were treated with cytokines only. Together, our study provides novel insights into the complex biological role of EVs and illustrates that aEVs and fEVs differentially support ex vivo expansion capacity of UCB-HSPCs. Together opening new means for the application of EVs in the discovery of therapeutics for more efficient ex vivo HSPC expansion.
机构:
Department of Hematopoiesis, Sanquin Research, Amsterdam, NetherlandsDepartment of Hematopoiesis, Sanquin Research, Amsterdam, Netherlands
Ghebes, Corina A.
Morhayim, Jess
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Department of Hematology, Erasmus MC, University Medical Center, Rotterdam, NetherlandsDepartment of Hematopoiesis, Sanquin Research, Amsterdam, Netherlands
Morhayim, Jess
Kleijer, Marion
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Department of Hematopoiesis, Sanquin Research, Amsterdam, NetherlandsDepartment of Hematopoiesis, Sanquin Research, Amsterdam, Netherlands
Kleijer, Marion
Koroglu, Merve
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Department of Hematopoiesis, Sanquin Research, Amsterdam, NetherlandsDepartment of Hematopoiesis, Sanquin Research, Amsterdam, Netherlands
Koroglu, Merve
Erkeland, Stefan J.
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Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, NetherlandsDepartment of Hematopoiesis, Sanquin Research, Amsterdam, Netherlands
Erkeland, Stefan J.
Hoogenboezem, Remco
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Department of Hematology, Erasmus MC, University Medical Center, Rotterdam, NetherlandsDepartment of Hematopoiesis, Sanquin Research, Amsterdam, Netherlands
Hoogenboezem, Remco
Bindels, Eric
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Department of Hematology, Erasmus MC, University Medical Center, Rotterdam, NetherlandsDepartment of Hematopoiesis, Sanquin Research, Amsterdam, Netherlands
Bindels, Eric
van Alphen, Floris P. J.
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Department of Molecular Hematology, Sanquin Research, Amsterdam, NetherlandsDepartment of Hematopoiesis, Sanquin Research, Amsterdam, Netherlands
van Alphen, Floris P. J.
van den Biggelaar, Maartje
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Department of Molecular Hematology, Sanquin Research, Amsterdam, NetherlandsDepartment of Hematopoiesis, Sanquin Research, Amsterdam, Netherlands
van den Biggelaar, Maartje
Nolte, Martijn A.
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Department of Hematopoiesis, Sanquin Research, Amsterdam, Netherlands
Department of Molecular Hematology, Sanquin Research, Amsterdam, NetherlandsDepartment of Hematopoiesis, Sanquin Research, Amsterdam, Netherlands
Nolte, Martijn A.
van der Eerden, Bram C. J.
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Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, NetherlandsDepartment of Hematopoiesis, Sanquin Research, Amsterdam, Netherlands
van der Eerden, Bram C. J.
Braakman, Eric
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Department of Hematology, Erasmus MC, University Medical Center, Rotterdam, NetherlandsDepartment of Hematopoiesis, Sanquin Research, Amsterdam, Netherlands
Braakman, Eric
Voermans, Carlijn
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Department of Hematopoiesis, Sanquin Research, Amsterdam, NetherlandsDepartment of Hematopoiesis, Sanquin Research, Amsterdam, Netherlands
Voermans, Carlijn
van de Peppel, Jeroen
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Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, NetherlandsDepartment of Hematopoiesis, Sanquin Research, Amsterdam, Netherlands
机构:
Symbiosis Int Deemed Univ, Symbiosis Ctr Stem Cell Res, Pune 412115, Maharashtra, IndiaSymbiosis Int Deemed Univ, Symbiosis Ctr Stem Cell Res, Pune 412115, Maharashtra, India
Budgude, Pallavi
Kale, Vaijayanti
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Symbiosis Int Deemed Univ, Symbiosis Ctr Stem Cell Res, Pune 412115, Maharashtra, IndiaSymbiosis Int Deemed Univ, Symbiosis Ctr Stem Cell Res, Pune 412115, Maharashtra, India
Kale, Vaijayanti
Vaidya, Anuradha
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Symbiosis Int Deemed Univ, Symbiosis Ctr Stem Cell Res, Pune 412115, Maharashtra, India
Symbiosis Int Deemed Univ, Symbiosis Sch Biol Sci, Pune 412115, Maharashtra, IndiaSymbiosis Int Deemed Univ, Symbiosis Ctr Stem Cell Res, Pune 412115, Maharashtra, India
机构:
Emory Univ, Div Pulm Allergy Crit Care & Sleep Med, Atlanta, GA 30322 USAEmory Univ, Div Pulm Allergy Crit Care & Sleep Med, Atlanta, GA 30322 USA
Nguyen, Doan C.
Lewis, Holly C.
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Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA
Emory Univ, Sch Med, Dept Hematol & Med Oncol, Atlanta, GA USAEmory Univ, Div Pulm Allergy Crit Care & Sleep Med, Atlanta, GA 30322 USA
Lewis, Holly C.
Joyner, Chester
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Emory Univ, Yerkes Natl Primate Res Ctr, Emory Vaccine Ctr, Int Ctr Malaria Res Educ & Dev, Atlanta, GA 30322 USAEmory Univ, Div Pulm Allergy Crit Care & Sleep Med, Atlanta, GA 30322 USA
Joyner, Chester
Warren, Vivien
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Emory Univ, Div Pulm Allergy Crit Care & Sleep Med, Atlanta, GA 30322 USAEmory Univ, Div Pulm Allergy Crit Care & Sleep Med, Atlanta, GA 30322 USA
Warren, Vivien
Xiao, Haopeng
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Georgia Inst Technol, Sch Chem & Biochem, Atlanta, GA 30332 USAEmory Univ, Div Pulm Allergy Crit Care & Sleep Med, Atlanta, GA 30322 USA
Xiao, Haopeng
Kissick, Haydn T.
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Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA
Emory Univ, Dept Urol, Atlanta, GA 30322 USAEmory Univ, Div Pulm Allergy Crit Care & Sleep Med, Atlanta, GA 30322 USA
Kissick, Haydn T.
Wu, Ronghu
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Georgia Inst Technol, Sch Chem & Biochem, Atlanta, GA 30332 USAEmory Univ, Div Pulm Allergy Crit Care & Sleep Med, Atlanta, GA 30322 USA
Wu, Ronghu
Galipeau, Jacques
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Univ Wisconsin, Dept Med, Madison, WI USA
Univ Wisconsin, Carbone Canc Ctr, Madison, WI USAEmory Univ, Div Pulm Allergy Crit Care & Sleep Med, Atlanta, GA 30322 USA
Galipeau, Jacques
Lee, F. Eun-Hyung
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Emory Univ, Div Pulm Allergy Crit Care & Sleep Med, Atlanta, GA 30322 USAEmory Univ, Div Pulm Allergy Crit Care & Sleep Med, Atlanta, GA 30322 USA
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Chinese Acad Med Sci, State Key Lab Translat Cardiovasc Med, Fuwai Hosp, Peking Union Med Coll, Beijing 100037, Peoples R China
Chinese Acad Med Sci, Cardiovasc Inst, Peking Union Med Coll, Beijing 100037, Peoples R ChinaChinese Acad Med Sci, State Key Lab Translat Cardiovasc Med, Fuwai Hosp, Peking Union Med Coll, Beijing 100037, Peoples R China
Tang, Yue
Cui, Yong-Chun
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Chinese Acad Med Sci, State Key Lab Translat Cardiovasc Med, Fuwai Hosp, Peking Union Med Coll, Beijing 100037, Peoples R China
Chinese Acad Med Sci, Cardiovasc Inst, Peking Union Med Coll, Beijing 100037, Peoples R ChinaChinese Acad Med Sci, State Key Lab Translat Cardiovasc Med, Fuwai Hosp, Peking Union Med Coll, Beijing 100037, Peoples R China
Cui, Yong-Chun
Wang, Xiao-Juan
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Beijing Union Hlth Co Ltd, Wu Stem Cells Med Ctr, Beijing 100070, Peoples R ChinaChinese Acad Med Sci, State Key Lab Translat Cardiovasc Med, Fuwai Hosp, Peking Union Med Coll, Beijing 100037, Peoples R China
Wang, Xiao-Juan
Wu, Ai-Li
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Chinese Acad Med Sci, State Key Lab Translat Cardiovasc Med, Fuwai Hosp, Peking Union Med Coll, Beijing 100037, Peoples R China
Chinese Acad Med Sci, Cardiovasc Inst, Peking Union Med Coll, Beijing 100037, Peoples R ChinaChinese Acad Med Sci, State Key Lab Translat Cardiovasc Med, Fuwai Hosp, Peking Union Med Coll, Beijing 100037, Peoples R China
Wu, Ai-Li
Hu, Guang-Fu
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Chinese Acad Med Sci, State Key Lab Translat Cardiovasc Med, Fuwai Hosp, Peking Union Med Coll, Beijing 100037, Peoples R China
Chinese Acad Med Sci, Cardiovasc Inst, Peking Union Med Coll, Beijing 100037, Peoples R ChinaChinese Acad Med Sci, State Key Lab Translat Cardiovasc Med, Fuwai Hosp, Peking Union Med Coll, Beijing 100037, Peoples R China
Hu, Guang-Fu
Luo, Fu-Liang
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Chinese Acad Med Sci, State Key Lab Translat Cardiovasc Med, Fuwai Hosp, Peking Union Med Coll, Beijing 100037, Peoples R China
Chinese Acad Med Sci, Cardiovasc Inst, Peking Union Med Coll, Beijing 100037, Peoples R ChinaChinese Acad Med Sci, State Key Lab Translat Cardiovasc Med, Fuwai Hosp, Peking Union Med Coll, Beijing 100037, Peoples R China
Luo, Fu-Liang
Sun, Jia-Kang
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Chinese Acad Med Sci, State Key Lab Translat Cardiovasc Med, Fuwai Hosp, Peking Union Med Coll, Beijing 100037, Peoples R China
Chinese Acad Med Sci, Cardiovasc Inst, Peking Union Med Coll, Beijing 100037, Peoples R ChinaChinese Acad Med Sci, State Key Lab Translat Cardiovasc Med, Fuwai Hosp, Peking Union Med Coll, Beijing 100037, Peoples R China
Sun, Jia-Kang
Sun, Jing
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Chinese Acad Med Sci, State Key Lab Translat Cardiovasc Med, Fuwai Hosp, Peking Union Med Coll, Beijing 100037, Peoples R China
Chinese Acad Med Sci, Cardiovasc Inst, Peking Union Med Coll, Beijing 100037, Peoples R ChinaChinese Acad Med Sci, State Key Lab Translat Cardiovasc Med, Fuwai Hosp, Peking Union Med Coll, Beijing 100037, Peoples R China
Sun, Jing
Wu, Li-Ke
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Beijing Union Hlth Co Ltd, Wu Stem Cells Med Ctr, Beijing 100070, Peoples R ChinaChinese Acad Med Sci, State Key Lab Translat Cardiovasc Med, Fuwai Hosp, Peking Union Med Coll, Beijing 100037, Peoples R China
机构:
Univ Calif Los Angeles, Los Angeles David Geffen Sch Med, Los Angeles, CA USAUniv Calif Los Angeles, Los Angeles David Geffen Sch Med, Los Angeles, CA USA
Yao, Qingping
Wang, James
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Univ Calif Los Angeles, Los Angeles David Geffen Sch Med, Los Angeles, CA USAUniv Calif Los Angeles, Los Angeles David Geffen Sch Med, Los Angeles, CA USA
Wang, James
Singh, Ram Raj
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Univ Calif Los Angeles, Los Angeles David Geffen Sch Med, Los Angeles, CA USAUniv Calif Los Angeles, Los Angeles David Geffen Sch Med, Los Angeles, CA USA