A magic kick for regeneration: role of mesenchymal stromal cell secretome in spermatogonial stem cell niche recovery

Abstract

BackgroundInjury of stem cell niches may disturb tissue homeostasis and regeneration coordinated by specific niche components. Yet, the mechanisms of stem cell niche restoration remain poorly understood. Herein, we examined the role of mesenchymal stromal cells (MSCs) as pivotal regulators of stem cell niche recovery focusing on the effects of their secretome.MethodsThe spermatogonial stem cell (SSC) niche was selected as a model. SSC niches were injured by inducing abdominal cryptorchidism in rats. Briefly, testes of anesthetized rats were elevated into the abdominal cavity through the inguinal canal for 14 days. After descent of testes, MSC or MSC secretome treatment was applied to the animals by local subtunical injections.ResultsLocal administration of MSC or MSC secretome was sufficient to recover spermatogenesis and production of functional germ cells. The effects of MSC and their secreted components were comparable, leading to restoration of Sertoli cell pools and recovery of Leydig cell secretory functions.ConclusionOur data suggest that MSCs mimic the functions of lost supportive cells within the stem cell niche, transiently providing paracrine stimuli for target cells and triggering tissue regenerative processes after damage.

Mesenchymal Stromal Cells as Critical Contributors to Tissue Regeneration

“…Therefore, injecting the MSC secretome can help attract lost Sertoli cells from the pools of progenitor cells. This assumption was indirectly supported by the restoration of the Sertoli cell pool without visible proliferation at the observed control points in vivo, as well as the stimulation of Sertoli cell migration by MSC secretion in vitro (Figueiredo et al, 2016;Sagaradze et al, 2019a).…”

“…In tissue-specific stem cell niches, MSCs might provide regulatory factors restricting the injury-induced responses of niche cells. Hence, we suppose that the ability of MSCs to restore the SSC niche due to the effects of their secretome, which we observed in a rat model of abdominal cryptorchidism (Sagaradze et al, 2019a ), could be at least partially mediated by secreted insulin-like growth factor-binding proteins (IGFBPs) (Kalinina et al, 2015a ). Niche damage causes hyperplasia of the interstitial compartment where Leydig cells localize and produce insulin-like growth factor 1 (IGF1) that is critical for the functioning of both SSCs and supporting cells.…”

“…One of the reasons may be the different sensitivity of MSCs to culture conditions. Hence, cell culture media can exert different effects on the secretory or differentiation potential of individual types of MSCs (Al-Saqi et al, 2014 ; Sagaradze et al, 2019a ). Another reason may be the persistent specialization of MSCs with respect to tissue-specific stem or resident cells (Tran et al, 2008 ; Pittenger et al, 2019 ).…”

Hypoxia-Preconditioned Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Mitigate Hypoglycemic Testicular Injury Induced by Insulin in Rats

“…Recently, intratesticular administration of stromal MSCs or MSC secretomes was sufficient to improve production of germ cells in experimentally induced cryptorchidism in rats [Sagaradze et al, 2019]. Also, two studies Dessouky/Gouda/Arafa/Elewa/Abo-Ouf/ Askar Cells Tissues Organs 2020;209:83-100 98 DOI: 10.1159/000510363 have shown that murine bone marrow MSCs can differentiate into testicular germ cells in immature rats [Nayernia et al, 2006] and in a mouse model of busulfaninduced infertility [Lue et al, 2007], while another two studies reported differentiation of transplanted bone marrow MSCs into Leydig cells [Yazawa et al, 2006;Xing et al, 2016].…”

Growth Factors in Regeneration and Regenerative Medicine: “the Cure and the Cause”

“…On the one hand, they possess an ability to proliferate and differentiate into a variety of tissue-specific cells, and on the other, they produce tissue-specific matrix and release soluble factors that orchestrate tissue renewal and repair (14,15). Deep involvement in tissue homeostasis maintenance makes these cells a lucrative object for study and potential application in regenerative medicine (16,17). Nevertheless, we still have much to find out about the factors and molecular machinery that regulates the functions of these cells (18).…”