PUBLICATION

Distinct Roles for Matrix Metalloproteinases 2 and 9 in Embryonic Hematopoietic Stem Cell Emergence, Migration, and Niche Colonization

Authors
Theodore, L.N., Hagedorn, E.J., Cortes, M., Natsuhara, K., Liu, S.Y., Perlin, J.R., Yang, S., Daily, M.L., Zon, L.I., North, T.E.
ID
ZDB-PUB-170419-6
Date
2017
Source
Stem Cell Reports   8(5): 1226-1241 (Journal)
Registered Authors
North, Trista, Perlin, Julie, Zon, Leonard I.
Keywords
Cxcl12, HSC/HSPC, Mmp2, Mmp9, PGE(2), extracellular matrix, fibronectin, inflammation, zebrafish
Datasets
GEO:GSE93818
MeSH Terms
  • Cell Movement*
  • Matrix Metalloproteinase 2/genetics
  • Matrix Metalloproteinase 2/metabolism*
  • Fibronectins/metabolism
  • Zebrafish/embryology
  • Zebrafish/metabolism
  • Embryonic Stem Cells/cytology*
  • Embryonic Stem Cells/metabolism
  • Embryonic Stem Cells/physiology
  • Stem Cell Niche*
  • Hematopoietic Stem Cells/cytology*
  • Hematopoietic Stem Cells/metabolism
  • Hematopoietic Stem Cells/physiology
  • Core Binding Factor Alpha 2 Subunit/metabolism
  • Animals
  • Extracellular Matrix/metabolism
  • Cell Proliferation
  • Zebrafish Proteins/metabolism
  • Matrix Metalloproteinase 9/genetics
  • Matrix Metalloproteinase 9/metabolism*
  • Chemokine CXCL12/metabolism
(all 21)
PubMed
28416284 Full text @ Stem Cell Reports
Abstract
Hematopoietic stem/progenitor cells (HSPCs) are formed during ontogeny from hemogenic endothelium in the ventral wall of the dorsal aorta (VDA). Critically, the cellular mechanism(s) allowing HSPC egress and migration to secondary niches are incompletely understood. Matrix metalloproteinases (MMPs) are inflammation-responsive proteins that regulate extracellular matrix (ECM) remodeling, cellular interactions, and signaling. Here, inhibition of vascular-associated Mmp2 function caused accumulation of fibronectin-rich ECM, retention of runx1/cmyb+ HSPCs in the VDA, and delayed caudal hematopoietic tissue (CHT) colonization; these defects were absent in fibronectin mutants, indicating that Mmp2 facilitates endothelial-to-hematopoietic transition via ECM remodeling. In contrast, Mmp9 was dispensable for HSPC budding, being instead required for proper colonization of secondary niches. Significantly, these migration defects were mimicked by overexpression and blocked by knockdown of C-X-C motif chemokine-12 (cxcl12), suggesting that Mmp9 controls CHT homeostasis through chemokine regulation. Our findings indicate Mmp2 and Mmp9 play distinct but complementary roles in developmental HSPC production and migration.
Genes / Markers
Figures
Figure Gallery (14 images) / 2
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Expression
Gene Antibody Fish Conditions Stage Qualifier Anatomy Assay Figure
DsRed2pd27Tg; zf741TgcontrolProtruding-mouthIHC
DsRed2pd27Tg; zf741TgcontrolProtruding-mouthIHC
DsRed2pd27Tg; zf741Tgchemical treatment by environment: MMP9 inhibitor IProtruding-mouthIHC
DsRed2pd27Tg; zf741Tgchemical treatment by environment: MMP9 inhibitor IProtruding-mouthIHC
DsRed2pd27Tg; zf741TgcontrolLong-pecIFL
DsRed2pd27Tg; zf741Tgchemical treatment by environment: N(2)-([biphenyl]-4-ylsulfonyl)-N-hydroxy-N(2)-isopropoxy-D-valinamideLong-pecIHC
DsRed2pd27Tg; zf741Tgchemical treatment by environment: N(2)-([biphenyl]-4-ylsulfonyl)-N-hydroxy-N(2)-isopropoxy-D-valinamideLong-pecIFL
DsRed2pd27Tg; zf741TgcontrolLong-pecIHC
DsRed2pd27Tg; zf741Tg + MO3-cxcl12acontrolProtruding-mouthIHC
DsRed2pd27Tg; zf741Tg + MO3-cxcl12achemical treatment by environment: MMP9 inhibitor IProtruding-mouthIHC
1 - 10 of 103
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Phenotype
Fish Conditions Stage Phenotype Figure
WTchemical treatment by environment: N(2)-([biphenyl]-4-ylsulfonyl)-N-hydroxy-N(2)-isopropoxy-D-valinamidePrim-25
WTchemical treatment by environment: N(2)-([biphenyl]-4-ylsulfonyl)-N-hydroxy-N(2)-isopropoxy-D-valinamidePrim-25
WTchemical treatment by environment: N(2)-([biphenyl]-4-ylsulfonyl)-N-hydroxy-N(2)-isopropoxy-D-valinamidePrim-25
WTchemical treatment by environment: N(2)-([biphenyl]-4-ylsulfonyl)-N-hydroxy-N(2)-isopropoxy-D-valinamideProtruding-mouth
WTchemical treatment by environment: N(2)-([biphenyl]-4-ylsulfonyl)-N-hydroxy-N(2)-isopropoxy-D-valinamideProtruding-mouth
WTchemical treatment by environment: N(2)-([biphenyl]-4-ylsulfonyl)-N-hydroxy-N(2)-isopropoxy-D-valinamideProtruding-mouth
WTchemical treatment by environment: N(2)-([biphenyl]-4-ylsulfonyl)-N-hydroxy-N(2)-isopropoxy-D-valinamideProtruding-mouth
WTchemical treatment by environment: N(2)-([biphenyl]-4-ylsulfonyl)-N-hydroxy-N(2)-isopropoxy-D-valinamideDay 5
WTchemical treatment by environment: N(2)-([biphenyl]-4-ylsulfonyl)-N-hydroxy-N(2)-isopropoxy-D-valinamideDay 5
WTchemical treatment by environment: N(2)-([biphenyl]-4-ylsulfonyl)-N-hydroxy-N(2)-isopropoxy-D-valinamideDay 5
1 - 10 of 74
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
c264TgTransgenic Insertion
    gl23TgTransgenic Insertion
      gl24TgTransgenic Insertion
        hu10535
          		Small Deletion
          i114TgTransgenic Insertion
            la2TgTransgenic Insertion
              la116TgTransgenic Insertion
                mik1TgTransgenic Insertion
                  pd27TgTransgenic Insertion
                    rw0410hTgTransgenic Insertion
                      1 - 10 of 19
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                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      Target Reagent Reagent Type
                      cxcl12aMO3-cxcl12aMRPHLNO
                      mmp2MO1-mmp2MRPHLNO
                      mmp9MO4-mmp9MRPHLNO
                      1 - 3 of 3
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                      Fish
                      Fish
                      fn1atl43c/tl43c
                      gl23Tg; i114Tg
                      la2Tg
                      la116Tg
                      la116Tg + MO1-mmp2
                      la116Tg + MO4-mmp9
                      mik1Tg
                      pd27Tg; zf169Tg
                      pd27Tg; zf169Tg + MO1-mmp2
                      pd27Tg; zf169Tg + MO4-mmp9
                      1 - 10 of 18
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                      Antibodies
                      Name Type Antigen Genes Isotypes Host Organism
                      Ab2-fnpolyclonal
                        		Rabbit
                        Ab4-h3polyclonal
                          		IgGRabbit
                          1 - 2 of 2
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                          Orthology
                          No data available
                          Engineered Foreign Genes
                          Marker Marker Type Name
                          DsRedEFGDsRed
                          DsRed2EFGDsRed2
                          EGFPEFGEGFP
                          GAL4EFGGAL4
                          GFPEFGGFP
                          mAGFPEFGmAGFP
                          mCherryEFGmCherry
                          NTREFGNTR
                          1 - 8 of 8
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                          Mapping
                          No data available
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                          Citation
                          Theodore, L.N., Hagedorn, E.J., Cortes, M., Natsuhara, K., Liu, S.Y., Perlin, J.R., Yang, S., Daily, M.L., Zon, L.I., North, T.E. (2017) Distinct Roles for Matrix Metalloproteinases 2 and 9 in Embryonic Hematopoietic Stem Cell Emergence, Migration, and Niche Colonization. Stem Cell Reports. 8(5):1226-1241.