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Matrix metalloproteinase 7 promoted Schwann cell migration and myelination after rat sciatic nerve injury

Wang, Hongkui, Zhang, Ping, Yu, Jun, Zhang, Fuchao, Dai, Wenzhao, Yi, Sheng·2019·Molecular Brain
DOI 10.1186/s13041-019-0516-6PMC PMC6889483
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Abstract

Schwann cells experience de-differentiation, proliferation, migration, re-differentiation and myelination, and participate in the repair and regeneration of injured peripheral nerves. Our previous sequencing analysis suggested that the gene expression level of matrix metalloproteinase 7 (MMP7), a Schwann cell-secreted proteolytic enzyme, was robustly elevated in rat sciatic nerve segments after nerve injury. However, the biological roles of MMP7 are poorly understood. Here, we exposed primary cultured Schwann cells with MMP7 recombinant protein and transfected siRNA against MMP7 into Schwann cells to examine the effect of exogenous and endogenous MMP7. Meanwhile, the effects of MMP7 in nerve regeneration after sciatic nerve crush in vivo were observed. Furthermore, RNA sequencing and bioinformatic analysis of Schwann cells were conducted to show the molecular mechanism behind the phenomenon. In vitro studies showed that MMP7 significantly elevated the migration rate of Schwann cells but did not affect the proliferation rate of Schwann cells. In vivo studies demonstrated that increased level of MMP7 contributed to Schwann cell migration and myelin sheaths formation after peripheral nerve injury. MMP7-mediated genetic changes were revealed by sequencing and bioinformatic analysis. Taken together, our current study demonstrated the promoting effect of MMP7 on Schwann cell migration and peripheral nerve regeneration, benefited the understanding of cellular and molecular mechanisms underlying peripheral nerve injury, and thus might facilitate the treatment of peripheral nerve regeneration in clinic.

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Fig. 1 The in vitro effect of MMP7 on Schwann cell proliferation. a-e Representative cell proliferation images of (a) non-treated Schwann cells (Con), b Schwann cells treated with MMP7 recombinant protein (MMP7), c Schwann cells transfected with siRNA control (si Con), d Schwann cells transfected with MMP7 siRNA1 (si1 MMP7), and (e) Schwann cells transfected with MMP7 siRNA2 (si2 MMP7). Scale bars represented 100 μm. f Relative MMP7 mRNA expression after transfection with siRNA control, MMP7 siRNA1, MMP7 siRNA2, and MMP7 siRNA3. Asterisks indicated significant different from siRNA control, * p-value < 0.05, n = 3. g Summarized proliferation rates of non-treated Schwann cells and Schwann cells treated with MMP7 recombinant protein. n = 3. h Summarized proliferation rates of Schwann cells transfected with siRNA control, MMP7 siRNA1, and MMP7 siRNA2. n = 3. i Schwann cells’ identification by histochemical staining. Specific marker S100 of Schwann cells is green, and Hoechst of nucleus is blue. Scale bars represented 100 μm and 20 μm respectively
Fig. 1 The in vitro effect of MMP7 on Schwann cell proliferation. a-e Representative cell proliferation images of (a) non-treated Schwann cells (Con), b Schwann cells treated with MMP7 recombinant protein (MMP7), c Schwann cells transfected with siRNA control (si Con), d Schwann cells transfected with MMP7 siRNA1 (si1 MMP7), and (e) Schwann cells transfected with MMP7 siRNA2 (si2 MMP7). Scale bars represented 100 μm. f Relative MMP7 mRNA expression after transfection with siRNA control, MMP7 siRNA1, MMP7 siRNA2, and MMP7 siRNA3. Asterisks indicated significant different from siRNA control, * p-value < 0.05, n = 3. g Summarized proliferation rates of non-treated Schwann cells and Schwann cells treated with MMP7 recombinant protein. n = 3. h Summarized proliferation rates of Schwann cells transfected with siRNA control, MMP7 siRNA1, and MMP7 siRNA2. n = 3. i Schwann cells’ identification by histochemical staining. Specific marker S100 of Schwann cells is green, and Hoechst of nucleus is blue. Scale bars represented 100 μm and 20 μm respectivelyCC BY · PubMed Central
Fig. 2 The in vitro effect of MMP7 on Schwann cell migration. a Representative cell migration images of non-treated Schwann cells (Con) and Schwann cells treated with MMP7 recombinant protein (MMP7) at 12 and 24 h after cell culture. Scale bars represented 100 μm. Histograms showed summarized migration rates of non-treated Schwann cells and Schwann cells treated with MMP7 recombinant protein. The asterisk indicated significant different from non-treated control, * p-value < 0.05, n = 3. b Representative cell migration images of Schwann cells transfected with siRNA control, MMP7 siRNA1, and MMP7 siRNA2 at 12 h after cell culture. Scale bars represented 100 μm. Histograms showed summarized migration rates of Schwann cells transfected with siRNA control, MMP7 siRNA1, and MMP7 siRNA2. Asterisks indicated significant different from siRNA control, * p-value < 0.05, n = 3. c Representative cell migration images of Schwann cells transfected with siRNA control, MMP7 siRNA1, and MMP7 siRNA2 at 24 h after cell culture. Scale bars represented 100 μm. Histograms showed summarized migration rates of Schwann cells transfected with siRNA control, MMP7 siRNA1, and MMP7 siRNA2. Asterisks indicated significant different from siRNA control, * p-value < 0.05, n = 3
Fig. 2 The in vitro effect of MMP7 on Schwann cell migration. a Representative cell migration images of non-treated Schwann cells (Con) and Schwann cells treated with MMP7 recombinant protein (MMP7) at 12 and 24 h after cell culture. Scale bars represented 100 μm. Histograms showed summarized migration rates of non-treated Schwann cells and Schwann cells treated with MMP7 recombinant protein. The asterisk indicated significant different from non-treated control, * p-value < 0.05, n = 3. b Representative cell migration images of Schwann cells transfected with siRNA control, MMP7 siRNA1, and MMP7 siRNA2 at 12 h after cell culture. Scale bars represented 100 μm. Histograms showed summarized migration rates of Schwann cells transfected with siRNA control, MMP7 siRNA1, and MMP7 siRNA2. Asterisks indicated significant different from siRNA control, * p-value < 0.05, n = 3. c Representative cell migration images of Schwann cells transfected with siRNA control, MMP7 siRNA1, and MMP7 siRNA2 at 24 h after cell culture. Scale bars represented 100 μm. Histograms showed summarized migration rates of Schwann cells transfected with siRNA control, MMP7 siRNA1, and MMP7 siRNA2. Asterisks indicated significant different from siRNA control, * p-value < 0.05, n = 3CC BY · PubMed Central
Fig. 3 The in vivo effect of MMP7 on Schwann cell proliferation. A and B Representative immunohistochemistry images of the longitude sections of rat sciatic nerve segments treated with A saline control and B MMP7 recombinant protein. Rat sciatic nerve segments were collected at 1, 7 and 14 days after nerve crush. Green indicated S100 staining of Schwann cells, red indicated Ki67 staining of proliferating cells, and blue indicated Hoechst staining of cell nuclei. Arrows indicated proliferating Schwann cells. Scale bars represented 50 μm. Boxed areas in (A and B) were demonstrated in higher magnifications in (A’ and B′), respectively. Arrows indicated proliferating Schwann cells too. Scale bars represented 20 μm. c Histogram of proliferation ratio in rats injected with saline or MMP7 recombinant protein at 1, 7 and 14 days after nerve crush, n = 3
Fig. 3 The in vivo effect of MMP7 on Schwann cell proliferation. A and B Representative immunohistochemistry images of the longitude sections of rat sciatic nerve segments treated with A saline control and B MMP7 recombinant protein. Rat sciatic nerve segments were collected at 1, 7 and 14 days after nerve crush. Green indicated S100 staining of Schwann cells, red indicated Ki67 staining of proliferating cells, and blue indicated Hoechst staining of cell nuclei. Arrows indicated proliferating Schwann cells. Scale bars represented 50 μm. Boxed areas in (A and B) were demonstrated in higher magnifications in (A’ and B′), respectively. Arrows indicated proliferating Schwann cells too. Scale bars represented 20 μm. c Histogram of proliferation ratio in rats injected with saline or MMP7 recombinant protein at 1, 7 and 14 days after nerve crush, n = 3CC BY · PubMed Central
Fig. 4 The in vivo effect of MMP7 on Schwann cell migration. A and B Representative immunohistochemistry images of the longitude sections of rat sciatic nerve segments treated with (A) saline control and (B) MMP7 recombinant protein. Rat sciatic nerve segments were collected at 1, 7 and 14 days after nerve crush. Red indicated S100 staining of Schwann cells, green indicated NF staining of axons, and blue indicated Hoechst staining of cell nuclei. Asterisks indicated migration from the proximal segment. Arrowheads indicated migration from the distal segment. Scale bars represented 500 μm. Boxed areas in (A and B) were shown in higher magnifications in (A’ and B’), respectively. Arrows indicated migrated Schwann cells. Scale bars represented 20 μm. c Summarized migration distances in rats injected with saline or MMP7 recombinant protein. Asterisk indicated significant different from saline control, * p-value < 0.05, n = 3
Fig. 4 The in vivo effect of MMP7 on Schwann cell migration. A and B Representative immunohistochemistry images of the longitude sections of rat sciatic nerve segments treated with (A) saline control and (B) MMP7 recombinant protein. Rat sciatic nerve segments were collected at 1, 7 and 14 days after nerve crush. Red indicated S100 staining of Schwann cells, green indicated NF staining of axons, and blue indicated Hoechst staining of cell nuclei. Asterisks indicated migration from the proximal segment. Arrowheads indicated migration from the distal segment. Scale bars represented 500 μm. Boxed areas in (A and B) were shown in higher magnifications in (A’ and B’), respectively. Arrows indicated migrated Schwann cells. Scale bars represented 20 μm. c Summarized migration distances in rats injected with saline or MMP7 recombinant protein. Asterisk indicated significant different from saline control, * p-value < 0.05, n = 3CC BY · PubMed Central
Fig. 5 The in vivo effect of MMP7 on axon and myelin sheath regeneration. a and b Representative immunohistochemistry images of the cross sections of rat sciatic nerve segments (crush sites) treated with saline at (a) 7 days and (b) 14 days after nerve crush. Red indicated S100 staining of Schwann cells and green indicated NF staining of axons. Scale bars represented 20 μm. c and d Representative immunohistochemistry images of rat sciatic nerve segments (crush sites) treated with MMP7 recombinant protein at (c) 7 days and (d) 14 days after nerve crush. Red indicated S100 staining of Schwann cells and green indicated NF staining of axons. Scale bars represented 20 μm. e Summarized numbers of axons in rats injected with saline or MMP7 recombinant protein. f Summarized numbers of myelin sheaths in rats injected with saline or MMP7 recombinant protein. g Summarized ratio of myelinated axons in rats injected with saline or MMP7 recombinant protein. Asterisk indicated significant different from saline control, * p-value < 0.05, n = 3
Fig. 5 The in vivo effect of MMP7 on axon and myelin sheath regeneration. a and b Representative immunohistochemistry images of the cross sections of rat sciatic nerve segments (crush sites) treated with saline at (a) 7 days and (b) 14 days after nerve crush. Red indicated S100 staining of Schwann cells and green indicated NF staining of axons. Scale bars represented 20 μm. c and d Representative immunohistochemistry images of rat sciatic nerve segments (crush sites) treated with MMP7 recombinant protein at (c) 7 days and (d) 14 days after nerve crush. Red indicated S100 staining of Schwann cells and green indicated NF staining of axons. Scale bars represented 20 μm. e Summarized numbers of axons in rats injected with saline or MMP7 recombinant protein. f Summarized numbers of myelin sheaths in rats injected with saline or MMP7 recombinant protein. g Summarized ratio of myelinated axons in rats injected with saline or MMP7 recombinant protein. Asterisk indicated significant different from saline control, * p-value < 0.05, n = 3CC BY · PubMed Central
Fig. 6 The in vivo effect of MMP7 on myelin sheath structure. a and b Representative transmission electron microscopy images of myelinated nerve fibers in the normal sciatic nerve. c and d Representative transmission electron microscopy images of myelinated nerve fibers in the sciatic nerve segments of rats treated with saline at 14 days after crush injury. e and f Representative transmission electron microscopy images of myelinated nerve fibers in the sciatic nerve segments of rats treated with MMP7 recombinant protein at 14 days after crush injury. Scale bars in (a, c, and e) represented 10 μm while scale bars in (b, d, and f) represented 200 nm. g Histogram of g-ratio (axon diameter to nerve fiber diameter) in rats injected with saline or MMP7 recombinant protein. Asterisk indicated significant different from saline control, ** p-value < 0.01, *** p-value < 0.001, n = 3
Fig. 6 The in vivo effect of MMP7 on myelin sheath structure. a and b Representative transmission electron microscopy images of myelinated nerve fibers in the normal sciatic nerve. c and d Representative transmission electron microscopy images of myelinated nerve fibers in the sciatic nerve segments of rats treated with saline at 14 days after crush injury. e and f Representative transmission electron microscopy images of myelinated nerve fibers in the sciatic nerve segments of rats treated with MMP7 recombinant protein at 14 days after crush injury. Scale bars in (a, c, and e) represented 10 μm while scale bars in (b, d, and f) represented 200 nm. g Histogram of g-ratio (axon diameter to nerve fiber diameter) in rats injected with saline or MMP7 recombinant protein. Asterisk indicated significant different from saline control, ** p-value < 0.01, *** p-value < 0.001, n = 3CC BY · PubMed Central
Fig. 7 MMP7 mediated gene expression changes. a Scatter plot of differentially expressed genes in MMP7-treated Schwann cells. Red color indicated up-regulation while green color indicated down-regulation. b Heatmap of the expression levels of these differentially expressed genes. Red color indicated high expression level while green color indicated low expression level. c GO biological process, molecular function, and cellular component terms of differentially expressed genes. The length of bar graph was correlated with the numbers of differentially expressed genes. d KEGG pathways of differentially expressed genes. The size of the circle was correlated with the numbers of differentially expressed genes. The color of the circle was correlated with q-value (red color indicated low q-value)
Fig. 7 MMP7 mediated gene expression changes. a Scatter plot of differentially expressed genes in MMP7-treated Schwann cells. Red color indicated up-regulation while green color indicated down-regulation. b Heatmap of the expression levels of these differentially expressed genes. Red color indicated high expression level while green color indicated low expression level. c GO biological process, molecular function, and cellular component terms of differentially expressed genes. The length of bar graph was correlated with the numbers of differentially expressed genes. d KEGG pathways of differentially expressed genes. The size of the circle was correlated with the numbers of differentially expressed genes. The color of the circle was correlated with q-value (red color indicated low q-value)CC BY · PubMed Central

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Metadata

Authors
Wang, H., Zhang, P., Yu, J., Zhang, F., Dai, W., & Yi, S.
ORCID
Yi, Sheng
Venue
Molecular Brain
Publisher
Springer Science and Business Media LLC
Published
2019-12
Volume
12
Issue
1
ISSN
1756-6606
DOI
10.1186/s13041-019-0516-6
PMC
PMC6889483
Cited by
25
References
1
Language
en
Licence
Funders
National Natural Science Foundation of China (31700926)

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