Skip to main content

Advertisement

SpringerLink
Log in

Adipose tissue-derived stem cell therapy for erectile dysfunction in rats: a systematic review and meta-analysis

  • Urology - Review
  • Published:
International Urology and Nephrology Aims and scope Submit manuscript

Abstract

Objective

We aimed to systematically assess the effect of adipose tissue-derived stem cell (ADSC) therapy and its influential factors on the treatment of erectile dysfunction (ED) in rats.

Methods

Two authors independently searched for published studies through PubMed and EMBASE from study inception until August 31, 2016. A meta-analysis was used to combine the effect estimate from the published studies. A subgroup analysis was performed to identify the effect of some influential factors. The pooled standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated by a fixed-effects or random-effects model analysis.

Results

Twenty studies with a total of 248 rats were included in this meta-analysis. The pooled analysis showed that ADSC therapy significantly increased the ratio of intracavernous pressure and mean arterial pressure (ICP/MAP; SMD 3.46, 95% CI 2.85–4.06; P < 0.001) compared to control therapy. The levels of neuronal nitric oxide synthase (nNOS; SMD 6.37, 95% CI 4.35–8.39; P < 0.001), the cavernous smooth muscle content (CSMC; SMD 3.65, 95% CI 2.65–4.65; P < 0.001), the ratio of cavernous smooth muscle and collagen (CSM/collagen; SMD 4.16, 95% CI 2.59–5.72; P < 0.001), and the cyclic guanosine monophosphate (cGMP; SMD 7.12, 95% CI 2.76–11.48; P = 0.001) were higher following ADSC therapy than following control therapy. Subgroup analysis showed that ADSCs modified by growth or neurotrophic factors significantly recovered erectile function (P < 0.001) compared with ADSC therapy.

Conclusion

The adequate data indicated that ADSC therapy recovered erectile function and regenerated cavernous structures in ED rats, and ADSCs modified by some growth and neurotrophic factors accelerated the recovery of erectile function and cavernous structures in ED rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. (1993) NIH consensus conference. Impotence. NIH consensus development panel on impotence. Jama 270:83–90

  2. Gratzke C, Angulo J, Chitaley K, Dai YT, Kim NN, Paick JS et al (2010) Anatomy, physiology, and pathophysiology of erectile dysfunction. J Sex Med 7:445–475. doi:10.1111/j.1743-6109.2009.01624.x

    Article  CAS  PubMed  Google Scholar 

  3. Alwaal A, Zaid UB, Lin CS, Lue TF (2015) Stem cell treatment of erectile dysfunction. Adv Drug Deliv Rev 82–83:137–144. doi:10.1016/j.addr.2014.11.012

    Article  PubMed  Google Scholar 

  4. Ayta IA, McKinlay JB, Krane RJ (1999) The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 84:50–56

    Article  CAS  PubMed  Google Scholar 

  5. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB (1994) Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 151:54–61

    CAS  PubMed  Google Scholar 

  6. Sand MS, Fisher W, Rosen R, Heiman J, Eardley I (2008) Erectile dysfunction and constructs of masculinity and quality of life in the multinational men’s attitudes to life events and sexuality (MALES) study. J Sex Med 5:583–594. doi:10.1111/j.1743-6109.2007.00720.x

    Article  PubMed  Google Scholar 

  7. McMahon CN, Smith CJ, Shabsigh R (2006) Treating erectile dysfunction when PDE5 inhibitors fail. BMJ Clin Res Ed 332:589–592. doi:10.1136/bmj.332.7541.589

    Article  Google Scholar 

  8. Li M, Li H, Ruan Y, Wang T, Liu J (2016) Stem cell therapy for diabetic erectile dysfunction in rats: a meta-analysis. PLoS ONE 11:e0154341. doi:10.1371/journal.pone.0154341

    Article  PubMed  PubMed Central  Google Scholar 

  9. Shan H, Chen F, Zhang T, He S, Xu L, Wei A (2015) Stem cell therapy for erectile dysfunction of cavernous nerve injury rats: a systematic review and meta-analysis. PLoS ONE 10:e0121428. doi:10.1371/journal.pone.0121428

    Article  PubMed  PubMed Central  Google Scholar 

  10. Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ et al (2001) Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 7:211–228. doi:10.1089/107632701300062859

    Article  CAS  PubMed  Google Scholar 

  11. Fandel TM, Albersen M, Lin G, Qiu X, Ning H, Banie L et al (2012) Recruitment of intracavernously injected adipose-derived stem cells to the major pelvic ganglion improves erectile function in a rat model of cavernous nerve injury. Eur Urol 61:201–210. doi:10.1016/j.eururo.2011.07.061

    Article  PubMed  Google Scholar 

  12. Zhang H, Yang R, Wang Z, Lin G, Lue TF, Lin CS (2011) Adipose tissue-derived stem cells secrete CXCL5 cytokine with neurotrophic effects on cavernous nerve regeneration. J Sex Med 8:437–446. doi:10.1111/j.1743-6109.2010.02128.x

    Article  CAS  PubMed  Google Scholar 

  13. Kang T, Jones TM, Naddell C, Bacanamwo M, Calvert JW, Thompson WE et al (2016) Adipose-derived stem cells induce angiogenesis via microvesicle transport of miRNA-31. Stem cells Transl Med 5:440–450. doi:10.5966/sctm.2015-0177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Matsuda K, Falkenberg KJ, Woods AA, Choi YS, Morrison WA, Dilley RJ (2013) Adipose-derived stem cells promote angiogenesis and tissue formation for in vivo tissue engineering. Tissue Eng A 19:1327–1335. doi:10.1089/ten.TEA.2012.0391

    Article  CAS  Google Scholar 

  15. Suga H, Glotzbach JP, Sorkin M, Longaker MT, Gurtner GC (2014) Paracrine mechanism of angiogenesis in adipose-derived stem cell transplantation. Ann Plast Surg 72:234–241. doi:10.1097/SAP.0b013e318264fd6a

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Guilak F, Lott KE, Awad HA, Cao Q, Hicok KC, Fermor B et al (2006) Clonal analysis of the differentiation potential of human adipose-derived adult stem cells. J Cell Physiol 206:229–237. doi:10.1002/jcp.20463

    Article  CAS  PubMed  Google Scholar 

  17. Gimble JM, Katz AJ, Bunnell BA (2007) Adipose-derived stem cells for regenerative medicine. Circ Res 100:1249–1260. doi:10.1161/01.res.0000265074.83288.09

    Article  CAS  PubMed  Google Scholar 

  18. Lund P, Pilgaard L, Duroux M, Fink T, Zachar V (2009) Effect of growth media and serum replacements on the proliferation and differentiation of adipose-derived stem cells. Cytotherapy 11:189–197. doi:10.1080/14653240902736266

    Article  CAS  PubMed  Google Scholar 

  19. Lin CS, Lin G, Lue TF (2012) Allogeneic and xenogeneic transplantation of adipose-derived stem cells in immunocompetent recipients without immunosuppressants. Stem cells Dev 21:2770–2778. doi:10.1089/scd.2012.0176

    Article  PubMed  PubMed Central  Google Scholar 

  20. Melief SM, Zwaginga JJ, Fibbe WE, Roelofs H (2013) Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem Cells Transl Med 2:455–463. doi:10.5966/sctm.2012-0184

    Article  PubMed  PubMed Central  Google Scholar 

  21. Garcia MM, Fandel TM, Lin G, Shindel AW, Banie L, Lin CS et al (2010) Treatment of erectile dysfunction in the obese type 2 diabetic ZDF rat with adipose tissue-derived stem cells. J Sex Med 7:89–98

    Article  PubMed  PubMed Central  Google Scholar 

  22. Liu G, Sun X, Bian J, Wu R, Guan X, Ouyang B et al (2013) Correction of diabetic erectile dysfunction with adipose derived stem cells modified with the vascular endothelial growth factor gene in a rodent diabetic model. PLoS ONE 8:e72790. doi:10.1371/journal.pone.0072790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lee SH, Kim IG, Jung AR, Shrestha KR, Lee JH, Park KD et al (2014) Combined effects of brain-derived neurotrophic factor immobilized poly-lactic-co-glycolic acid membrane with human adipose-derived stem cells and basic fibroblast growth factor hydrogel on recovery of erectile dysfunction. Tissue Eng A 20:2446–2454. doi:10.1089/ten.TEA.2013.0495

    Article  CAS  Google Scholar 

  24. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ Clin Res Ed 339:b2535. doi:10.1136/bmj.b2535

    Article  Google Scholar 

  25. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Controll Clin Trials 7:177–188

    Article  CAS  Google Scholar 

  26. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748

    CAS  PubMed  Google Scholar 

  27. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101

    Article  CAS  PubMed  Google Scholar 

  28. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ Clin Res Ed 315:629–634

    Article  CAS  Google Scholar 

  29. Albersen M, Fandel TM, Lin G, Lin CS, Lue TF (2010) The effect of injection of adipose-derived stem cells or stem cell lysate in the corpus cavernosum on erectile function in a rat model of cavernous nerve injury. J Urol 183:e343–e344

    Article  Google Scholar 

  30. Qiu X, Villalta J, Ferretti L, Fandel TM, Albersen M, Lin G et al (2012) Effects of intravenous injection of adipose-derived stem cells in a rat model of radiation therapy-induced erectile dysfunction. J Sex Med 9:1834–1841. doi:10.1111/j.1743-6109.2012.02753.x

    Article  PubMed  PubMed Central  Google Scholar 

  31. Piao S, Kim IG, Lee JY, Hong SH, Kim SW, Hwang TK et al (2012) Therapeutic effect of adipose-derived stem cells and BDNF-immobilized PLGA membrane in a rat model of cavernous nerve injury. J Sex Med 9:1968–1979. doi:10.1111/j.1743-6109.2012.02760.x

    Article  CAS  PubMed  Google Scholar 

  32. Gokce A, Abd Elmageed ZY, Lasker GF, Bouljihad M, Kim H, Trost LW et al (2014) Adipose tissue-derived stem cell therapy for prevention and treatment of erectile dysfunction in a rat model of Peyronie’s disease. Andrology 2:244–251. doi:10.1111/j.2047-2927.2013.00181.x

    Article  CAS  PubMed  Google Scholar 

  33. You D, Jang MJ, Lee J, Suh N, Jeong IG, Sohn DW et al (2013) Comparative analysis of periprostatic implantation and intracavernosal injection of human adipose tissue-derived stem cells for erectile function recovery in a rat model of cavernous nerve injury. Prostate 73:278–286. doi:10.1002/pros.22567

    Article  CAS  PubMed  Google Scholar 

  34. Jeong HH, Piao S, Ha JN, Kim IG, Oh SH, Lee JH et al (2013) Combined therapeutic effect of udenafil and adipose-derived stem cell (ADSC)/brain-derived neurotrophic factor (BDNF)-membrane system in a rat model of cavernous nerve injury. Urology 81(5):1108.e7–e14. doi:10.1016/j.urology.2013.01.022

    Article  Google Scholar 

  35. Kim IG, Piao S, Lee JY, Hong SH, Hwang TK, Kim SW et al (2013) Effect of an adipose-derived stem cell and nerve growth factor-incorporated hydrogel on recovery of erectile function in a rat model of cavernous nerve injury. Tissue Eng A 19:14–23. doi:10.1089/ten.TEA.2011.0654

    Article  CAS  Google Scholar 

  36. Ying C, Yang M, Zheng X, Hu W, Wang X (2013) Effects of intracavernous injection of adipose-derived stem cells on cavernous nerve regeneration in a rat model. Cell Mol Neurobiol 33:233–240. doi:10.1007/s10571-012-9890-7

    Article  PubMed  Google Scholar 

  37. Bae JH, Shrestha KR, Park YH, Kim IG, Piao S, Jung AR et al (2014) Comparison between subcutaneous injection of basic fibroblast growth factor-hydrogel and intracavernous injection of adipose-derived stem cells in a rat model of cavernous nerve injury. Urology 84(5):1248.e1–e7. doi:10.1016/j.urology.2014.07.028

    Article  Google Scholar 

  38. Xu Y, Guan R, Lei H, Li H, Wang L, Gao Z et al (2014) Therapeutic potential of adipose-derived stem cells-based micro-tissues in a rat model of postprostatectomy erectile dysfunction. J Sex Med 11:2439–2448. doi:10.1111/jsm.12636

    Article  CAS  PubMed  Google Scholar 

  39. Yang R, Fang F, Wang J, Guo H (2015) Adipose-derived stem cells ameliorate erectile dysfunction after cavernous nerve cryoinjury. Andrology 3:694–701. doi:10.1111/andr.12047

    Article  CAS  PubMed  Google Scholar 

  40. You D, Jang MJ, Kim BH, Song G, Lee C, Suh N et al (2015) Comparative study of autologous stromal vascular fraction and adipose-derived stem cells for erectile function recovery in a rat model of cavernous nerve injury. Eur Urol Suppl 14:e45

    Article  Google Scholar 

  41. Zhou F, Hui Y, Xu Y, Lei H, Yang B, Guan R et al (2016) Effects of adipose-derived stem cells plus insulin on erectile function in streptozotocin-induced diabetic rats. Int Urol Nephrol 48:657–669. doi:10.1007/s11255-016-1221-3

    Article  CAS  PubMed  Google Scholar 

  42. Liu T, Peng Y, Jia C, Fang X, Li J, Zhong W (2015) Hepatocyte growth factor-modified adipose tissue-derived stem cells improve erectile function in streptozotocin-induced diabetic rats. Growth Factors 33:282–289. doi:10.3109/08977194.2015.1077825

    Article  CAS  PubMed  Google Scholar 

  43. Wang X, Liu C, Li S, Xu Y, Chen P, Liu Y et al (2015) Hypoxia precondition promotes adipose-derived mesenchymal stem cells based repair of diabetic erectile dysfunction via augmenting angiogenesis and neuroprotection. PLoS ONE 10:e0118951. doi:10.1371/journal.pone.0118951

    Article  PubMed  PubMed Central  Google Scholar 

  44. Huang YC, Kuo YH, Huang YH, Chen CS, Ho DR, Shi CS (2016) The effects of adipose-derived stem cells in a rat model of tobacco-associated erectile dysfunction. PLoS ONE 11:e0156725. doi:10.1371/journal.pone.0156725

    Article  PubMed  PubMed Central  Google Scholar 

  45. Zhou F, Hui Y, Xin H, Xu YD, Lei HE, Yang BC et al (2016) Therapeutic effects of adipose-derived stem cells-based microtissues on erectile dysfunction in streptozotocin-induced diabetic rats. Asian J Androl. doi:10.4103/1008-682x.182817

    Google Scholar 

  46. Walter U, Gambaryan S (2009) cGMP and cGMP-dependent protein kinase in platelets and blood cells. Handb Exp Pharmacol. doi:10.1007/978-3-540-68964-5_23

    PubMed  Google Scholar 

  47. Mas M (2010) Molecular mechanisms of penile erection. Arch Esp Urol 63:589–598

    Article  PubMed  Google Scholar 

  48. Burnett AL (1997) Nitric oxide in the penis: physiology and pathology. J Urol 157:320–324

    Article  CAS  PubMed  Google Scholar 

  49. Musicki B, Ross AE, Champion HC, Burnett AL, Bivalacqua TJ (2009) Posttranslational modification of constitutive nitric oxide synthase in the penis. J Androl 30:352–362. doi:10.2164/jandrol.108.006999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lue TF (2000) Erectile dysfunction. N Engl J Med 342:1802–1813. doi:10.1056/nejm200006153422407

    Article  CAS  PubMed  Google Scholar 

  51. Lin CS, Xin Z, Dai J, Huang YC, Lue TF (2013) Stem-cell therapy for erectile dysfunction. Expert Opin Biol Ther 13:1585–1597. doi:10.1517/14712598.2013.847085

    Article  CAS  PubMed  Google Scholar 

  52. Qiu X, Fandel TM, Ferretti L, Albersen M, Zhang H, Lin G et al (2012) Both immediate and delayed intracavernous injection of autologous adipose-derived stromal vascular fraction enhances recovery of erectile function in a rat model of cavernous nerve injury. Eur Urol 62:720–727

    Article  PubMed  PubMed Central  Google Scholar 

  53. Ryu JK, Tumurbaatar M, Jin HR, Kim WJ, Kwon MH, Piao S et al (2012) Intracavernous delivery of freshly isolated stromal vascular fraction rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse. J Sex Med 9:3051–3065. doi:10.1111/j.1743-6109.2012.02962.x

    Article  PubMed  Google Scholar 

  54. Das ND, Song KM, Yin GN, Batbold D, Kwon MH, Kwon KD et al (2014) Xenogenic transplantation of human breast adipose-derived stromal vascular fraction enhances recovery of erectile function in diabetic mice. Biol Reprod 90:66. doi:10.1095/biolreprod.113.115113

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Epidemiology, College of Public Heath, Zhengzhou University, Zhengzhou, 450001, Henan, China

    Quan-liang Hou, Meng-ying Ge, Dan-dan Tian, Lian-ke Wang, Hui-zi Tian, Wen-hua Wang & Wei-dong Zhang

  2. School of Public Health and Tropical Medicine, New Orleans, LA, 70112, USA

    Cheng-da Zhang

Authors
  1. Quan-liang Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meng-ying Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cheng-da Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dan-dan Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lian-ke Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hui-zi Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wen-hua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wei-dong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

WD Zhang and QL Hou designed the study. LK Wang and DD Tian designed the search strategies and performed the literatures search. CD Zhang, HZ Tian, and WH Wang selected the literatures and extracted the data. QL Hou and MY Ge analyzed the data. QL Hou and MY Ge wrote the paper. All authors approved the submitted and final versions.

Corresponding author

Correspondence to Wei-dong Zhang.

Ethics declarations

Conflict of interest

The authors have declared that no conflict of interests exists.

Additional information

Quan-liang Hou and Meng-ying Ge: co-first author.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hou, Ql., Ge, My., Zhang, Cd. et al. Adipose tissue-derived stem cell therapy for erectile dysfunction in rats: a systematic review and meta-analysis. Int Urol Nephrol 49, 1127–1137 (2017). https://doi.org/10.1007/s11255-017-1590-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11255-017-1590-2

Keywords

Search

Navigation