Table 1.
Animal study: data extraction results.
| Reference | Stem cell | Type/source | Co-intervention | Total rats | Experiment randomization | Type of injury | Route (average time of treatment 2–4 h after injury) | Dose | Assessment interval | ED function assessment | Histological/Molecular assessment |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1. Zheng et al.
13
China |
ADSC | Allogenic SD rat Groin |
ICA II | 42 SD | Divided into six groups a. Sham group = 7 b. BCNI only = 7 c. BCNI + PBS = 7 d. BCNI + ADSC = 7 e. BCNI + ICI II = 7 f. BCNI + ICI II + ADSC = 7 |
BCNI (transection injury) | ICI, ICA II intragastric | ADSCs (5 × 105) ICA (4.5 mg/kg/day) |
1 week | ICP value and ICP/MAP ratio | Western blotting CCK 8 assay RNA immunoprecipitation NOS content |
| 2. Yang et al.
14
China |
ADSC | Allogenic SD rat inguinal fat pad |
rAd expressing hBDNF | 40 SD | Divided into four groups a. Sham group = 10 b. BCNI only = 10 c. ADSCs infected with lenti-GFP = 10 d. ADSCs infected with lenti-GFP = 10 |
BCNI (crush) | ICI | ADSCs infected with lenti-GFP (1 × 106 in 20 µl) and lenti-rBDNF (1 × 106 in 20 µl) | 4 weeks | Maximal ICP/MAP ratio | Western blot Masson trichrome staining NOS content |
| 3. Yang et al.
15
China |
ADSC | Allogenic Rat epididymis |
Nil | 36 SD | Divided into six groups a. Sham group = 6 b. PBS = 6 c. ADSC = 6 d. VEGF (ADSC-V) = 6 e. GDNF (ADSC-G) = 6 f. VEGF and GDNF (ADSC-G&V) = 6 |
BCNI (crush injury) | MPG | Cell-fibrin scaffolds (1.5 × 106 cells, 100 µl per rat) were prepared | 2 weeks | Mean ICP | Western blotting |
| 4. Chen et al.
16
China |
ADSC Pluripotent stem cells |
Human adipose tissue | iMSC and human adMSC | Not available | Divided into four groups a. Sham operation (sham group) b. adMSC group (adipose-derived MSC group) c. Induced pluripotent stem cell-derived MSC (iMSC group). d. PBS Group (PBS only group) |
BCNI (crush injury) | Intracavernosal (ICI) | 1 × 106 adMSC cells 1 × 106 iMSC cells Both in 20 µl of PBS |
4 weeks | ICP/MAP ratio | Western blot Masson trichrome staining Immunoreaction detection |
| 5. Ying et al.
17
China |
ADSC NAS |
Allogenic Rat inguinal fat |
Nil | 45 SD rats | Divided into three groups a. Sham group = 15 b. BCNI with PBS = 15 c. BCNI with NAS = 15 |
BCNI (crush injury) | ICI | One million NAS | 4 weeks | Maximal ICP/MAP ratio | Masson s trichrome staining Toluidine staining NOS content |
| 6. Wu et al.
18
Taiwan |
BM-MSC | Allogenic Rat femur |
SPC | 24 SD rats | Divided into three groups a. Sham group = 8 b. Vehicle group = 8 c. SPC group = 8 |
BCNI (crush injury) | ICI | NA | 4 weeks | Maximal ICP/MAP ratio | Histology NOS content Immunoflorescence |
| 7. Matsuda et al.
19
Japan |
BM-MSCs | Allogenic Rat bone marrow |
Nil | 18 SD rats | Divided into three groups a. Sham group = 6 b. Vehicle derived MSC = 6 c. BM-MSC = 6 |
BCNI (electric coagulation) | Intravenous, right jugular vein | 1.0 × 106 cells | 4 weeks | ICP/MAP ratio, with ICP-AUC analysis | Masson s trichrome staining Fluorogold study Green fluorescence |
| 8. Ouyang et al.
20
China |
MSCs and MSC exosomes | Allogenic Rat bone marrow |
Nil | 32 SD rats | Divided into four groups a. Sham = 8 b. PBS = 8 c. MSC = 8 d. MSC exosomes = 8 |
BCNI (crush injury) | ICI | MSC cells: 1.5 × 106
MSC exosomes: 100 µg |
4 weeks | Maximal ICP increase | Western blotting TUNEL staining |
| 9. Li et al.
21
China |
ADSCs and BMSCs | NA | Exosomes derived from ADSC (ADSC-Exo) and BMSC (BMSC-Exo) | 48 SD rats | Divided into four groups a. Sham group = 12 b. BCNI + vehicle MSC = 12 c. BCNI + exosomes derived from ADSCs (ADSC-Exo group) = 12 d. BCNI + BMSC-derived exosomes (BMSC-Exo) = 12 |
BCNI (crush injury) | ICI | 100 µg proteins of exosomes derived from ADSC/BMSC | 3 weeks | Maximal ICP/MAP ratio | Masson s trichrome staining Imaging fluorescence |
| 10. Zheng et al.
22
China |
ADSCs | Allogenic SD rats |
ICA II promoted the differentiation of ADSCs to SCs | 36 SD rats | Divided into six groups a. Sham (n = 6) b. BCNI (n = 6) c. PBS (n = 6) d. ADSCs (n = 6) e. ICA II (n = 6) f. ICA II + ADSCs (n = 6) |
BCNI (crush injury) | ICI and intragastric for ICA II | ADSC, 1 × 106 cells, ICA II (4.5 mg/kg/day) | 4 weeks | ICP and MAP | Western blotting qRT-PCR |
| 11. Wu et al. 23 China | ADSCs | Allogenic SD rats |
Nanotechnology-assisted (Nano-ADSC)-injected group with an external magnetic field | 40 SD rats | Divided into four groups: a. Sham (n = 10) b. BCNI (n = 10) c. ADSCs (n = 10) d. Nano-ADSC (n = 10) |
BCNI (crush injury) | ICI | 2 × 105 cells | 4 weeks | ICP/MAP ratio | Western blotting Immunohistochemistry In Vivo ADSC tracing |
| 12. Chen et al.
24
China |
ADSCs | Allogenic SD rats |
Nil | 40 SD rats | Divided into four groups a. Sham = 32 b. BCNI = 32 c. PBS = 8 d. ADSC = 8 (four rats died in Sham and BCNI groups) |
BCNI (crush injury) | Intracavernosal (ICI) | 2 × 105 cells | 4 weeks | ICP/MAP ratio | Masson s trichrome staining Fluorescence Staining |
| 13. Fang et al.
25
China |
BM-MSC (r-MSC) | Allogenic Rat bone marrow |
Neural d-MSCs Using trans-retinoic acid for differentiation |
50 SD rats | Divided into five groups (10 in each) a. sham operation group = 10 b. BCNI + ICI of r-BM-MSCs (IC group) = 10 c. PPI of r-BM-MSCs (IP group) = 10 d. PPI of d-MSCs (IP-d group) = 10 e. PPI of PBS (PBS group) = 10 |
BCNI (crush injury) | Intracavernosal (ICI) and PPI | 1 × 106 cells | 2 weeks | ICP, MAP, and AUC | Western blotting Immunofluorescence staining Immunohistochemical staining |
| 14. Jeon et al.
26
Korea |
ADSC | Human fat | Low energy SWT | 50 SD rats | Divided into five groups a. Sham group = 10 b. BCNI group = 10 c. BCNI + ADSC group = 10 d. BCNI + SWT group = 10 e. BCNI + SWT + ADSC group = 10 |
BCNI (crush injury) | Around injured cavernous injury | 1 × 106 cells | 4 weeks | ICP, ICP/MAP | Immunostaining, Western blotting, and a cyclic guanosine monophosphate assay |
| 15. Song et al.
27
China |
Umbilical cord-MSCs | hUCB mesenchymal stem cells (hUCB-MSCs) | BDNF | 42 SD rats | Divided into four groups Group A: sham operation sham + PBS, n = 6 Group B: BCNI + PBS, 12 Group C: BCNI + hUCB-MSCs, n = 12 Group D: BCNI + BDNF-hUCB-MSCs n = 12 |
BCNI (electric coagulation) | Intracavernosal (ICI) | 2 × 106 cells | 4 weeks | ICP/MAP | Western blotting |
| 16. Yang et al.
28
China |
ADSC | Allogenic rats | Nil | 39 SD rats | Divided into three groups a. Sham group = 13 b. Cryo group = 13 c. ADSC group = 13 |
BCNI (cryoinjury) | ICI | 1 × 106 cells | 4 weeks | ICP/MAP | Western blotting Immunofluorescence staining Immunohistochemical staining |
| 17. Kim et al.
29
South Korea |
BM-MSCs | Human (iliac crest) | SPION-MSC | 30 SD rats | Divided into three groups a. Sham group = 10 b. BCNI group = 10 c. SPION-MSC group = 10 |
BCNI (crush injury) | ICI | 1 × 106 cells | 2 and 4 weeks | ICP/MAP | MRI Histological evaluation |
| 18. Lee et al.
30
South Korea |
ADSCs | Human | BDNF | 75 SD rats | Divided into five groups a. Normal (N) group = 15 b. Saline application = 15 c. Fibroblast growth factor-hydrogel injection (bFGF) = 15 d. ADSC application covered with BDNF – membrane after BCNI (ADSC/BDNF) = 15 e. The co-administration of bFGF-hydrogel injection and BDNF-membrane with ADSC after BDNF (bFGF + ADSC/BDNF) = 15 |
BCNI (crush injury) | ICI | 1 × 106 cells | 4 weeks | ICP/MAP | Masson s trichrome staining Western blotting NOS expression |
| 19. Kim et al.
31
South Korea |
ADSCs | Human | NGF-hydrogel | 25 SD rats | Divided into five groups a. Sham = 5 b. BCNI + Saline application = 5 c. BCNI + ADSCs = 5 d. BCNI + NGF = 5 e. BCNI + ADSC + NGF = 5 |
BCNI (crush injury) | MPG | 1 × 106 cells | 4 weeks | ICP/MAP ratio | Immunoflorescence staining Western Blot for eNOS and nNOS |
| 20. You et al.
32
South Korea |
BM-MSC | Human (hBMSC) | Nil | 40 SD rats | Divided into four groups a. Sham = 10 b. ICI of PBS + PPI of fibrin sealent = 10 c. hBMSCs (ICI group) = 10 d. hBMSCs (PPI + ICI group) = 10 |
BCNI (dissection) | MPG and ICI | 1 × 106 cells | 4 weeks | ICP/MAP ratio | Western blotting Immunohistochemical analysis |
| 21. You et al.
33
South Korea |
ADSCs | Human | Fibrin scaffolds for periprostatic injection of ADSCs | 60 SD rats | Divided into six groups a. Sham = 10 b. BCNI = 10 c. ICI of PBS + PPI of fibrin sealent = 10 d. PPI of ADSC-seeded fibrin sealant = 10 e. ICI of ADSC = 10 f. PPI of ADSC-seeded fibrin sealant and ICI of ADSCs = 10 |
BCNI (dissection) | MPG and ICI | 1 × 106 cells | 4 weeks | ICP/MAP ratio with AUC | Western blotting Immunohistochemical analysis |
| 22. Jeong et al.
34
South Korea |
ADSC | Human | BDNF, oral Udenafil in desired group | 30 SD rats | Divided into five groups a. Sham group = 6 b. BCNI = 6 c. BCNI + Oral Udenafil = 6 d. BCNI + ADSC + BDNF = 6 e. BCNI + ADSC + BDNF + Oral Udenafil = 6 |
BCNI (crush injury) | Local application to injured nerve | 1 × 106 cells | 4 weeks | ICP/MAP ratio | Immunohistochemical analysis Masson s trichrome cGMP eNOS |
| 23. Qiu et al.
35
USA |
ADSC | Autologous rat | Adipose-derived SVF (immediate group received SVF after BCNI, delayed group received SVF after 4 weeks) | 89 SD rats | Divided into four groups a. Sham group = 26 b. BCNI + Saline = 23 c. BCNI + Immediate SVF = 17 d. BCNI + Delayed SVF = 23 |
BCNI (crush injury) | ICI | 2 × 106 cells | 12 weeks | ICP | Masson s trichrome |
| 24. Kim et al.
36
South Korea |
BM-MSCs | Allogenic rats (femur/tibia) | Matrixen used (it is a collagen-based biocompatible polymer and it has been used widely as scaffolds in medical field) | 50 SD rats | Divided into five groups a. Sham group = 5 b. BCNI = 10 c. BCNI + MSCs = 10 d. BCNI + Matrixen = 10 e. BCNI + MSC + Matrixen = 10 |
BCNI (crush injury) | MPG | 1 × 106 cells Matrixen 20 µl |
4 weeks | ICP/MAP ratio | PKH-26/NGF co-staining into cavernous nerve, histological and immunohistochemical analysis |
| 25. Kim et al.
37
South Korea |
BM-MSCs | Allogenic rats (femur/tibia) |
BDNF (rAd/hBDNF represents MSCs infected with rAd expressing human BDNF) | 40 SD rats | Divided into four groups a. Sham group = 10 b. BCNI = 10 c. BCNI + MSC = 10 d. BCNI + MSC infected with rAd/hBDNF = 10 |
BCNI (crush injury) | MPG | 1 × 106 cells | 4 weeks | ICP/MAP ratio | Masson s trichrome staining eNOS and nNOS protein expression by Western blotting |
| 26. Woo et al.
38
South Korea |
Muscle derived-MSC (MD-MSC) |
Allogenic white rats (derived from femoral muscles) | MD-MSC was labeled with PKH-26 fluorescent cell linker | 15 White rats | Divided rats into three groups a. Sham group = 5 b. BCNI = 5 c. BCNI + MD-MSC = 5 |
BCNI (transection injury) | ICI | 1 × 106 cells | 4 weeks | ICP | Histology Measurement of cGMP |
| 27. Albersen et al.
39
USA |
ADSC | Autologous (paratesticular pad of adipose tissue) | Nil | 32 SD rats | Divided rats into four groups a. Sham group + PBS = 8 b. BCNI + PBS = 8 c. BCNI + ADSC Lysate = 8 d. BCNI + ADSC = 8 |
BCNI (crush injury) | ICI | 1 × 106 cells | 4 weeks | ICP/MAP | Histology TUNEL staining |
| 28. Kim et al.
40
USA |
MD-MSC and HBSS used (Hanks’ Balanced Salt Solution) | Allogenic (MD-MSC from gastrocnemius muscle of female SD rat) | Rat MDC were transduced with retrovirus carrying the β-galactosidase reporter gene | 30 SD rats | Divided rats into five groups a. Sham = 6 b. BCNI + MDSC + HBSS = 6 (2 weeks) c. BCNI + MDSC + HBSS = 6 (4 weeks) d. BCNI + HBSS = 6 (2 weeks) e. BCNI + HBSS = 6 (4 weeks) |
BCNI (transection injury) | ICI | 1 × 106 cells | 2/4 weeks | ICP | Histology |
| 29. Bochinski et al.
41
USA |
Embryonic stem cells Embryonal |
Allogenic rats (from blastocyst) | NES (embryonic stem cells were induced to differentiate into neural cells by transfecting them with BDNF) | 26 SD rats | Divided into four groups a. Sham group = 5 b. BCNI + culture medium into CC = 8 c. BCNI + NES to MPG = 4 d. BCNI + NES to CC = 9 |
BCNI (crush injury) | ICI and MPG | 500 µl (10,000 cells/ml) | 3 months | ICP | Histochemical analysis for NOS-containing fibers, tyrosine hydroxylase, and neurofilament staining |
adMSC, adipose MSC; ADSC, adipose-derived stem cell; AUC, Area under curve; BCNI, bilateral cavernous nerve injury; BDNF, brain-derived neurotrophic factor; BM-MSCs, bone marrow–derived stem cells; CC, corpus cavernosum; CCK8,Cell Counting Kit-8; cGMP, cyclic guanosine monophosphate; d-MSCs, differentiated MSCs; ED, erectile dysfunction; bFGF, Basic fibroblast growth factor; eNOS, endothelial nitric oxide synthase; GDNF, glial cell-derived nerve growth factor; GFP, green fluorescent protein; hBDNF, human brain–derived neurotrophic factor; hBMSC,human bone marrow stem cells;HBSS, Hanks Balanced Salt solution; hUCB, human umbilical cord blood; ICA II, Icariside II; ICI, intracavernosal injection; ICP, intracavernosal pressure; iMSC, induced pluripotent stem cell–derived MSC; MAP, mean arterial pressure; MD-MSC, Muscle derived stem cells; MPG, major pelvic ganglion; MRI, magnetic resonance imaging; MSC, mesenchymal stem cell; NA, not available; NAS, neural-like cells from adipose-derived stem cells; NES, neural stem cells; NGF-hydrogel, nerve growth factor–incorporated hyaluronic acid–based hydrogel; nNOS, neuronal nitric oxide synthase; NOS, nitric oxide synthase; PBS, phosphate-buffered saline; PKH-26, red-fluorescent dye; PPI, periprostatic implantation; qRT-PCR, quantitative reverse transcription polymerase chain reaction; rAd, recombinant adenoviruses; SCs, Schwann cells; SD, Sprague-Dawley rats; SPC, smooth muscle progenitor; SPION-MSC, super-paramagnetic iron oxide nanoparticle labeling was performed for MSC; SVF, stromal vascular fraction; SWT, shock wave therapy; TUNEL, terminal deoxynucleotidyltransferase-mediated nick-end labeling; VEGF, vascular endothelial growth factor.