A meta-analysis of the effectiveness of cellular therapy for treating azoospermia in animal models: are we ready for clinical application?

M Azizoğlu*, M Gazzaneo**, S Perez Bertolez***, S Klyuev****, MH Okur*****, TO Kamçı*****, D Gürel******, O Aubert*******, E Karakaş********, S Yuksel*********, AP Zorba Yıldız**********, C Gigena***********, M Escolino************, S Shehata*************, C Esposito************

*Istanbul Esenyurt State Hospital, Department of Pedaitric Surgery, Istanbul, Turkey; Istinye University, Department of Stem Cell and Tissue Engineering, Istanbul, Turkey. Pediatric Surgery Meta Analysis Study Group (PESMA) (pesmastudy@gmail.com); Ped
**Dipartimento Pediatrico, UO Chirurgia Pediatrica, ASST Spedali Civili di Brescia, Università di Brescia, Italia. Specialist Neonatal and Paediatric Surgery, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. Pediatric Surgery
***Pediatric Surgery Departament. Hospital Sant Joan de Déu. Barcelona. Spain. Pediatric Surgery Meta Analysis Study Group (PESMA)
****Department of Pediatric Surgery, AO GK MEDSI, 102151 Moscow, Russia. Pediatric Surgery Meta Analysis Study Group (PESMA) (pesmastudy@gmail.com); Pediatric Surgery Stem Cell Application Study Group (PESSCA) (pedsurgstemcell@gmail.com)
*****Dicle University, Department of Pediatric Surgery, Diyarbakir, Turkey. Pediatric Surgery Meta Analysis Study Group (PESMA) (pesmastudy@gmail.com); Pediatric Surgery Stem Cell Application Study Group (PESSCA) (pedsurgstemcell@gmail.com)
******Prof. Dr. Cemil Tascioglu City Hospital, Department of Pediatric Surgery, Istanbul, Turkey; Pediatric Surgery Meta Analysis Study Group (PESMA)
*******Department of Pediatric Surgery, University Hospital Leipzig, Leipzig, Germany. Pediatric Surgery Meta-Analysis Study Group (PESMA)
********Başakşehir Çam and Sakura City Hospital, Department of Pediatric Surgery, Istanbul, Turkey; Pediatric Surgery Meta Analysis Study Group (PESMA) (pesmastudy@gmail.com); Pediatric Surgery Stem Cell Application Study Group (PESSCA) (pedsurgstemcell@gmai
*********Başakşehir Çam and Sakura City Hospital, Department of Pediatric Surgery, Istanbul, Turkey; Pediatric Surgery Meta Analysis Study Group (PESMA) (pesmastudy@gmail.com); Pediatric Surgery Stem Cell Application Study Group (PESSCA) (pedsurgstemcell@gmai
**********Istinye University, Vocational School of Health Care Services; Istinye University, Department of Stem Cell and Tissue Engineering, Istanbul, Turkey.
***********Cincinnati Children's, Pediatric Surgery, Cincinnati, OH, USA. Pediatric Surgery Meta Analysis Group (PESMA), Istanbul, Turkey
************Division of Pediatric Surgery, Federico II University Hospital, Naples, Italy; Pediatric Surgery Meta Analysis Study Group (PESMA)
*************Alexandria University, Department of Pediatric Surgery, Egypt; Pediatric Surgery Meta Analysis Study Group (PESMA)

Aim:

This study aims to evaluate the therapeutic effectiveness of stem cell transplantation (SCT) for azoospermia in animal models through a systematic review and meta-analysis.

Methods:

We conducted a literature review to find studies evalauate the therapeutic effectiveness of stem cell transplantation for azoospermia. A meta-analysis was conducted to systematically compile and compare factors. We conducted a comprehensive literature search using several databases, including Ovid Medline, Cochrane, PubMed, Web of Sciences, EMBASE, and SCOPUS until August 2024. Our search targeted keywords including “stem cell”,”testis”, “azoospermia”, “testicular torsion”, “testis ischemia reperfusion”.

Results:

A total of 20 preclinical studies included. A higher Vasa expression was seen in the SCT group than in the control group (p<0.05). Umbilical cord mesenchymal stem cells (UC-MSCs) exhibited the strongest impact on Vasa gene expression (p<0.05). No significant differences were observed in the therapeutic effects between iPSCs and the three different adult stem cell (ASC) types (p>0.05). Studies demonstrated significantly higher Scp3 levels in the SCT group compared to the control group (p < 0.05). Injection into the tunica albuginea group resulted in the highest level of spermatogenesis and repair of damaged testis (p<0.05). Urine-derived stem cells, spermatogonial stem cells, and amniotic fluid-derived stem cells demonstrated substantial therapeutic effects.

Conclusions:

The study concludes that stem cell transplantation, effectively enhances spermatogenesis and testis repair in azoospermia models, with significant therapeutic potential demonstrated across various stem cell types.

Keywords: Testis, kök hücre, azoospermia

Hayvan modellerinde azoospermi tedavisinde hücresel terapinin etkinliğine yönelik bir meta-analiz: klinik uygulamaya hazır mıyız?

M Azizoğlu*, M Gazzaneo**, S Perez Bertolez***, S Klyuev****, MH Okur*****, TO Kamçı*****, D Gürel******, O Aubert*******, E Karakaş********, S Yuksel*********, AP Zorba Yıldız**********, C Gigena***********, M Escolino************, S Shehata*************, C Esposito************

*Istanbul Esenyurt State Hospital, Department of Pedaitric Surgery, Istanbul, Turkey; Istinye University, Department of Stem Cell and Tissue Engineering, Istanbul, Turkey. Pediatric Surgery Meta Analysis Study Group (PESMA) (pesmastudy@gmail.com); Ped
**Dipartimento Pediatrico, UO Chirurgia Pediatrica, ASST Spedali Civili di Brescia, Università di Brescia, Italia. Specialist Neonatal and Paediatric Surgery, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. Pediatric Surgery
***Pediatric Surgery Departament. Hospital Sant Joan de Déu. Barcelona. Spain. Pediatric Surgery Meta Analysis Study Group (PESMA)
****Department of Pediatric Surgery, AO GK MEDSI, 102151 Moscow, Russia. Pediatric Surgery Meta Analysis Study Group (PESMA) (pesmastudy@gmail.com); Pediatric Surgery Stem Cell Application Study Group (PESSCA) (pedsurgstemcell@gmail.com)
*****Dicle University, Department of Pediatric Surgery, Diyarbakir, Turkey. Pediatric Surgery Meta Analysis Study Group (PESMA) (pesmastudy@gmail.com); Pediatric Surgery Stem Cell Application Study Group (PESSCA) (pedsurgstemcell@gmail.com)
******Prof. Dr. Cemil Tascioglu City Hospital, Department of Pediatric Surgery, Istanbul Turkey; Pediatric Surgery Meta Analysis Study Group (PESMA)
*******Department of Pediatric Surgery, University Hospital Leipzig, Leipzig, Germany. Pediatric Surgery Meta-Analysis Study Group (PESMA)
********Başakşehir Çam and Sakura City Hospital, Department of Pediatric Surgery, Istanbul, Turkey; Pediatric Surgery Meta Analysis Study Group (PESMA) (pesmastudy@gmail.com); Pediatric Surgery Stem Cell Application Study Group (PESSCA) (pedsurgstemcell@gmai
*********Başakşehir Çam and Sakura City Hospital, Department of Pediatric Surgery, Istanbul, Turkey; Pediatric Surgery Meta Analysis Study Group (PESMA) (pesmastudy@gmail.com); Pediatric Surgery Stem Cell Application Study Group (PESSCA) (pedsurgstemcell@gmai
**********Istinye University, Vocational School of Health Care Services; Istinye University, Department of Stem Cell and Tissue Engineering, Istanbul, Turkey.
***********Cincinnati Children's, Pediatric Surgery, Cincinnati, OH, USA. Pediatric Surgery Meta Analysis Group (PESMA), Istanbul, Turkey
************Division of Pediatric Surgery, Federico II University Hospital, Naples, Italy; Pediatric Surgery Meta Analysis Study Group (PESMA)
*************Alexandria University, Department of Pediatric Surgery, Egypt; Pediatric Surgery Meta Analysis Study Group (PESMA)

Amaç:

Bu çalışma, sistematik bir derleme ve meta-analiz yoluyla hayvan modellerinde azoospermi tedavisinde kök hücre naklinin (SCT) terapötik etkinliğini değerlendirmeyi amaçlamaktadır.

Yöntemler:

Azoospermi için kök hücre naklinin terapötik etkinliğini değerlendiren çalışmaları bulmak amacıyla bir literatür taraması gerçekleştirdik. Faktörleri sistematik olarak derlemek ve karşılaştırmak için bir meta-analiz yapıldı. Ovid Medline, Cochrane, PubMed, Web of Sciences, EMBASE ve SCOPUS gibi çeşitli veritabanlarını kullanarak kapsamlı bir literatür taraması yaptık ve Ağustos 2024'e kadar olan çalışmaları inceledik. Aramamız, “kök hücre”, “testis”, “azoospermi”, “testis torsiyonu”, “testis iskemi reperfüzyonu” gibi anahtar kelimelere odaklandı.

Bulgular:

Toplam 20 preklinik çalışma dahil edilmiştir. SCT grubunda kontrol grubuna göre daha yüksek Vasa ekspresyonu gözlendi (p<0.05). Umbilikal kord mezenkimal kök hücreleri (UC-MSC'ler), Vasa gen ekspresyonu üzerinde en güçlü etkiyi gösterdi (p<0.05). iPSC'ler ile üç farklı yetişkin kök hücre (ASC) tipi arasında terapötik etkiler açısından anlamlı fark gözlenmedi (p>0.05). Çalışmalar, SCT grubunda kontrol grubuna göre anlamlı derecede daha yüksek Scp3 seviyeleri gösterdi (p<0.05). Tunika albugineaya enjeksiyon, spermatogenez ve hasarlı testis onarımında en yüksek seviyeyi sağladı (p<0.05). İdrar kaynaklı kök hücreler, spermatogonyal kök hücreler ve amniyotik sıvı kaynaklı kök hücreler önemli terapötik etkiler gösterdi.

Sonuçlar:

Çalışma, kök hücre naklinin azoospermi modellerinde spermatogenez ve testis onarımını etkin bir şekilde artırdığını ve çeşitli kök hücre tiplerinde önemli terapötik potansiyel gösterdiğini ortaya koymaktadır.

Anahtar Kelimeler: Testis, stem cell, azoospermia