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

ABSTRACT: BACKGROUND:Injury 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. METHODS:The 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. RESULTS:Local 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. CONCLUSION:Our 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.

SUBMITTER: Sagaradze G

PROVIDER: S-EPMC6873442 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Sagaradze Georgy G Basalova Nataliya N Kirpatovsky Vladimir V Ohobotov Dmitry D Nimiritsky Peter P Grigorieva Olga O Popov Vladimir V Kamalov Armais A Tkachuk Vsevolod V Efimenko Anastasia A

Stem cell research & therapy 20191121 1

<h4>Background</h4>Injury 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.<h4>Methods</h4>The spermatogonial stem cell (SSC) niche was selected as a model. SSC niches were injured by inducing abdominal c ...[more]

PMID: 31753023

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Project description:BackgroundEfficient and sustained hematopoietic recovery after hematopoietic stem cell or bone marrow transplantation is supported by paracrine signaling from specific subpopulations of mesenchymal stromal cells (MSCs). Here, we considered whether in vitro mechanopriming of human MSCs could be administered to predictively and significantly improve in vivo hematopoietic recovery after irradiation injury.MethodsFirst, we implemented regression modeling to identify eight MSC-secreted proteins that correlated strongly with improved rescue from radiation damage, including hematopoietic recovery, in a murine model of hematopoietic failure. Using these partial least squares regression (PLSR) model parameters, we then predicted recovery potential of MSC populations that were culture expanded on substrata of varying mechanical stiffness. Lastly, we experimentally validated these predictions using an in vitro co-culture model of hematopoiesis and using new in vivo experiments for the same irradiation injury model used to generate survival predictions.ResultsMSCs grown on the least stiff (elastic moduli ~ 1 kPa) of these polydimethylsiloxane (PDMS) substrata secreted high concentrations of key proteins identified in regression modeling, at concentrations comparable to those secreted by minor subpopulations of MSCs shown previously to be effective in supporting such radiation rescue. We confirmed that these MSCs expanded on PDMS could promote hematopoiesis in an in vitro co-culture model with hematopoietic stem and progenitor cells (HSPCs). Further, MSCs cultured on PDMS of highest stiffness (elastic moduli ~ 100 kPa) promoted expression of CD123+ HSPCs, indicative of myeloid differentiation. Systemic administration of mechanoprimed MSCs resulted in improved mouse survival and weight recovery after bone marrow ablation, as compared with both standard MSC expansion on stiffer materials and with biophysically sorted MSC subpopulations. Additionally, we observed recovery of white blood cells, platelets, and red blood cells, indicative of complete recovery of all hematopoietic lineages.ConclusionsThese results demonstrate that computational techniques to identify MSC biomarkers can be leveraged to predict and engineer therapeutically effective MSC phenotypes defined by mechanoprimed secreted factors, for translational applications including hematopoietic recovery.

Dataset Information

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

Publications

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

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