Quantitative proteomics revealed extensive microenvironmental changes after stem cell transplantation in ischemic stroke

doi:10.1007/s11684-021-0842-9

Front. Med.

2022, Vol. 16

Issue (3) : 429-441 https://doi.org/10.1007/s11684-021-0842-9

RESEARCH ARTICLE

Quantitative proteomics revealed extensive microenvironmental changes after stem cell transplantation in ischemic stroke

Yao Chen^1,^2,^3,⁷, Fahuan Song^1,^2,³, Mengjiao Tu^1,^2,^3,⁸, Shuang Wu^1,^2,³, Xiao He^1,^2,³, Hao Liu^1,^2,³, Caiyun Xu^1,^2,³, Kai Zhang^1,^2,³, Yuankai Zhu^1,^2,³, Rui Zhou^1,^2,³, Chentao Jin^1,^2,³, Ping Wang^5,⁶, Hong Zhang^1,^2,^3,^4,^5,⁶(

), Mei Tian^1,^2,³(

)

¹. Department of Nuclear Medicine and Medical PET Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
². Institute of Nuclear Medicine and Molecular Imaging, Zhejiang University, Hangzhou 310009, China
³. Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou 310009, China
⁴. Shanxi Medical University, Taiyuan 030001, China
⁵. Key Laboratory for Biomedical Engineering of Ministry of Education, Zhejiang University, Hangzhou 310027, China
⁶. College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou 310027, China
⁷. Department of Radiology, Zhejiang Hospital, Hangzhou 310030, China
⁸. Department of PET Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China

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Abstract

The local microenvironment is essential to stem cell-based therapy for ischemic stroke, and spatiotemporal changes of the microenvironment in the pathological process provide vital clues for understanding the therapeutic mechanisms. However, relevant studies on microenvironmental changes were mainly confined in the acute phase of stroke, and long-term changes remain unclear. This study aimed to investigate the microenvironmental changes in the subacute and chronic phases of ischemic stroke after stem cell transplantation. Herein, induced pluripotent stem cells (iPSCs) and neural stem cells (NSCs) were transplanted into the ischemic brain established by middle cerebral artery occlusion surgery. Positron emission tomography imaging and neurological tests were applied to evaluate the metabolic and neurofunctional alterations of rats transplanted with stem cells. Quantitative proteomics was employed to investigate the protein expression profiles in iPSCs-transplanted brain in the subacute and chronic phases of stroke. Compared with NSCs-transplanted rats, significantly increased glucose metabolism and neurofunctional scores were observed in iPSCs-transplanted rats. Subsequent proteomic data of iPSCs-transplanted rats identified a total of 39 differentially expressed proteins in the subacute and chronic phases, which are involved in various ischemic stroke-related biological processes, including neuronal survival, axonal remodeling, antioxidative stress, and mitochondrial function restoration. Taken together, our study indicated that iPSCs have a positive therapeutic effect in ischemic stroke and emphasized the wide-ranging microenvironmental changes in the subacute and chronic phases.

Keywords ischemic stroke microenvironment induced pluripotent stem cells (iPSCs) positron emission tomography (PET) quantitative proteomics

Corresponding Author(s): Hong Zhang,Mei Tian

Just Accepted Date: 16 April 2021 Online First Date: 13 July 2021 Issue Date: 18 July 2022

Cite this article:

Yao Chen,Fahuan Song,Mengjiao Tu, et al. Quantitative proteomics revealed extensive microenvironmental changes after stem cell transplantation in ischemic stroke[J]. Front. Med., 2022, 16(3): 429-441.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0842-9
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I3/429

Fig.1 Schematic of the experimental procedures. The methods for evaluating the therapeutic response of stem cells include PET imaging, neurological tests, immunofluorescence, and HE staining. The methods for microenvironment study include quantitative iTRAQ-LC-MS/MS analysis and Western blot analysis.

Fig.2 Improved glucose metabolism and neurologic function after stem cell transplantation. (A) Representative ¹⁸F-FDG PET images and (B) semiquantitative analysis of glucose metabolism of cerebral ischemic rats demonstrate metabolic recovery after stem cell transplantation. Images are shown in the axial view. White arrows show the infarcted area. **P<0.01 compared with the PBS group. (C) Neurological scores show the neurological function restoration of cerebral ischemic rats in each group. *P<0.05, **P<0.01 compared with the PBS group; ^#P<0.05 compared with the NSCs group. (D) Serial ¹¹C-MET PET images of cerebral ischemic rats after transplantation in each group. Images are shown in the coronal view. (E) HE staining of tissues in the peri-infarct zone in each group. Scale bar= 100 µm.

Fig.3 Differentiation of transplanted stem cells in vivo. Representative immunofluorescent images indicate the differentiation of transplanted iPSCs (A) and NSCs (B) in the cortex adjacent to the ischemic striatum. The GFP-positive iPSCs and NSCs are shown in green ﬂuorescence; the NeuN-, GFAP-, and vWF-positive cells are shown in red; the DAPI-stained nuclei are shown in blue. White arrows show the NeuN-, GFAP-, or vWF-positive transplanted stem cells in merged images. Scale bar= 100 µm.

Fig.4 Expression profiles of differentially expressed proteins. The volcano plots show 2294 and 2303 identified proteins between the iPSCs group and the PBS group on days 7 (A) and 14 (B), respectively. Each dot represents a protein. The threshold for differential expression (fold change= 1.2 or 0.83 and significance level of P value<0.05) is indicated by the blue dashed lines. The significantly upregulated and downregulated proteins are highlighted in red and blue, respectively. (C) Heatmap showing the expression levels of 39 differentially expressed proteins in the cerebral ischemic area on days 7 and 14. *, significantly expressed between the iPSCs group and the PBS group.

UniProt ID	Gene symbol	Protein name	Ratio (iPSCs/PBS)	P value
Neuronal survival
Q4QQV8	Chmp5	Charged multivesicular body protein 5^a	2.00	0.03
Q01986	Map2k1	Dual specificity mitogen-activated protein kinase kinase 1^b	1.22	0.02
B1WBW4	Armc10	Armadillo repeat-containing protein 10^a	0.68	0.03
P04775	Scn2a	Sodium channel protein type 2 subunit α^b	0.77	0.01
G3V7J1	Clstn3	Calsyntenin-3^b	0.78	0.02
Q5M7A7	Cnrip1	CB1 cannabinoid receptor-interacting protein 1^a	0.82	0.01
F1LP76	Ikbkap	Elongator complex protein 1^b	0.83	0.01
Axonal remodeling
P22057	Ptgds	Prostaglandin-H2 D-isomerase^a	1.72	0.04
Q6J4I0	Ppp1r1b	Protein phosphatase 1 regulatory subunit 1B^a	1.41	0.00
Q562C6	Lztfl1	Leucine zipper transcription factor-like protein 1^a	1.20	0.00
F1LP34	Anp32b	Acidic leucine-rich nuclear phosphoprotein 32 family member B^b	0.81	0.03
P47875	Csrp1	Cysteine and glycine-rich protein 1^a	0.83	0.01
Mitochondrial function
Q62760	Tomm20	Mitochondrial import receptor subunit TOM20 homolog^a	1.32	0.04
Q4QRB0	Gale	Galactose-4-epimerase, UDP, isoform CRA_a^a	1.31	0.01
A0A0G2JSR6	Gng7	Guanine nucleotide binding protein G(I)/G(S)/G(O) subunit γ-7^a	1.22	0.00
P32089	Slc25a1	Tricarboxylate transport protein, mitochondrial^b	1.20	0.01
G3V9J7	Rabep1	RabGTPase binding effector protein 1^b	0.79	0.02
A0A096MIV5	Abcf2	Protein Abcf2^b	0.81	0.03
G3V784	Adpgk	ADP-dependent glucokinase, isoform CRA_a^b	0.81	0.04
Q5RKH2	Galk1	Galactokinase 1^b	0.83	0.02
Oxidative stress
D3ZCZ9	LOC100912599	NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial^b	1.27	0.03
Q3KRD8	Eif6	Eukaryotic translation initiation factor 6^b	0.80	0.04
Q6AXX6	Fam213a	Redox-regulatory protein FAM213A^a	0.82	0.01
Q6AXX5	Rdh11	Protein Rdh11^b	0.82	0.03
Others/unknown
A1L114	Fga	Fga protein^a	1.70	0.01
P14480	Fgb	Fibrinogen beta chain^a	1.65	0.02
D4A250	RGD1563620	Protein RGD1563620^b	1.41	0.01
A0A0G2QC17	Pdp1	Protein phosphatase 2C, magnesium dependent, catalytic subunit, isoform CRA_a^a	1.36	0.03
Q63041	A1m	α-1-macroglobulin^a	1.36	0.04
Q68FY4	Gc	Group specific component^a	1.34	0.00
A0A0G2JUR5	Mprip	Myosin phosphatase Rho-interacting protein^a	1.27	0.02
M0RCT5	Eml1	Echinoderm microtubule-associated protein-like 1^a	1.21	0.03
D3ZWW5	Slc30a9	Protein Slc30a9^a	1.21	0.04
Q80X08	Fam21	WASH complex subunit FAM21^b	0.70	0.04
Q6PDU6	Hbb	β-glo^a	0.70	0.02
A0A0G2JXY6	Scn1b	Sodium channel subunit β-1^b	0.76	0.04
A0A0G2K5H2	Clvs1	Clavesin-1^b	0.79	0.00
P84039	Enpp5	Ectonucleotidepyrophosphatase/phosphodiesterase family member 5^b	0.82	0.00
F1M3P6	Scai	Protein Scai^a	0.82	0.02

Tab.1 Quantitative information of the differentially expressed proteins from the iTRAQ data

Fig.5 GO annotations of differentially expressed proteins on days 7 (A) and 14 (B). GO annotations cover three categories including biological process, cellular component, and molecular function. Only the top five terms in each category are shown.

Fig.6 Western blot analysis of the selected differentially expressed proteins. (A) Representative Western blots of GALE and MEK1 and (B) corresponding quantitative analyses of expression levels in the cerebral ischemic tissues on days 7 and 14. The expression levels of GALE and MEK1 in the iPSCs group were significantly higher than those in the PBS group on days 7 and 14. *P<0.05, **P<0.01 compared with the PBS group.

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