Transcriptional responses of skeletal stem/progenitor cells to hindlimb unloading and recovery correlate with localized but not systemic multi-systems impacts

Abstract Disuse osteoporosis (DO) results from mechanical unloading of weight-bearing bones and causes structural changes that compromise skeletal integrity, leading to increased fracture risk. Although bone loss in DO results from imbalances in osteoblast vs. osteoclast activity, its effects on ske...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Cori N. Booker, Christopher L. Haga, Siddaraju V. Boregowda, Jacqueline Strivelli, Donald G. Phinney
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Biotechnology TP248.13-248.65 Physiology QP1-981
Acceso en línea:	https://doaj.org/article/3c13a6b3b57648d89fc2e9a8526667c9
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:3c13a6b3b57648d89fc2e9a8526667c9
record_format	dspace
spelling	oai:doaj.org-article:3c13a6b3b57648d89fc2e9a8526667c92021-11-28T12:26:57ZTranscriptional responses of skeletal stem/progenitor cells to hindlimb unloading and recovery correlate with localized but not systemic multi-systems impacts10.1038/s41526-021-00178-02373-8065https://doaj.org/article/3c13a6b3b57648d89fc2e9a8526667c92021-11-01T00:00:00Zhttps://doi.org/10.1038/s41526-021-00178-0https://doaj.org/toc/2373-8065Abstract Disuse osteoporosis (DO) results from mechanical unloading of weight-bearing bones and causes structural changes that compromise skeletal integrity, leading to increased fracture risk. Although bone loss in DO results from imbalances in osteoblast vs. osteoclast activity, its effects on skeletal stem/progenitor cells (SSCs) is indeterminate. We modeled DO in mice by 8 and 14 weeks of hindlimb unloading (HU) or 8 weeks of unloading followed by 8 weeks of recovery (HUR) and monitored impacts on animal physiology and behavior, metabolism, marrow adipose tissue (MAT) volume, bone density and micro-architecture, and bone marrow (BM) leptin and tyrosine hydroxylase (TH) protein expression, and correlated multi-systems impacts of HU and HUR with the transcript profiles of Lin−LEPR+ SSCs and mesenchymal stem cells (MSCs) purified from BM. Using this integrative approach, we demonstrate that prolonged HU induces muscle atrophy, progressive bone loss, and MAT accumulation that paralleled increases in BM but not systemic leptin levels, which remained low in lipodystrophic HU mice. HU also induced SSC quiescence and downregulated bone anabolic and neurogenic pathways, which paralleled increases in BM TH expression, but had minimal impacts on MSCs, indicating a lack of HU memory in culture-expanded populations. Although most impacts of HU were reversed by HUR, trabecular micro-architecture remained compromised and time-resolved changes in the SSC transcriptome identified various signaling pathways implicated in bone formation that were unresponsive to HUR. These findings indicate that HU-induced alterations to the SSC transcriptome that persist after reloading may contribute to poor bone recovery.Cori N. BookerChristopher L. HagaSiddaraju V. BoregowdaJacqueline StrivelliDonald G. PhinneyNature PortfolioarticleBiotechnologyTP248.13-248.65PhysiologyQP1-981ENnpj Microgravity, Vol 7, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biotechnology TP248.13-248.65 Physiology QP1-981
spellingShingle	Biotechnology TP248.13-248.65 Physiology QP1-981 Cori N. Booker Christopher L. Haga Siddaraju V. Boregowda Jacqueline Strivelli Donald G. Phinney Transcriptional responses of skeletal stem/progenitor cells to hindlimb unloading and recovery correlate with localized but not systemic multi-systems impacts
description	Abstract Disuse osteoporosis (DO) results from mechanical unloading of weight-bearing bones and causes structural changes that compromise skeletal integrity, leading to increased fracture risk. Although bone loss in DO results from imbalances in osteoblast vs. osteoclast activity, its effects on skeletal stem/progenitor cells (SSCs) is indeterminate. We modeled DO in mice by 8 and 14 weeks of hindlimb unloading (HU) or 8 weeks of unloading followed by 8 weeks of recovery (HUR) and monitored impacts on animal physiology and behavior, metabolism, marrow adipose tissue (MAT) volume, bone density and micro-architecture, and bone marrow (BM) leptin and tyrosine hydroxylase (TH) protein expression, and correlated multi-systems impacts of HU and HUR with the transcript profiles of Lin−LEPR+ SSCs and mesenchymal stem cells (MSCs) purified from BM. Using this integrative approach, we demonstrate that prolonged HU induces muscle atrophy, progressive bone loss, and MAT accumulation that paralleled increases in BM but not systemic leptin levels, which remained low in lipodystrophic HU mice. HU also induced SSC quiescence and downregulated bone anabolic and neurogenic pathways, which paralleled increases in BM TH expression, but had minimal impacts on MSCs, indicating a lack of HU memory in culture-expanded populations. Although most impacts of HU were reversed by HUR, trabecular micro-architecture remained compromised and time-resolved changes in the SSC transcriptome identified various signaling pathways implicated in bone formation that were unresponsive to HUR. These findings indicate that HU-induced alterations to the SSC transcriptome that persist after reloading may contribute to poor bone recovery.
format	article
author	Cori N. Booker Christopher L. Haga Siddaraju V. Boregowda Jacqueline Strivelli Donald G. Phinney
author_facet	Cori N. Booker Christopher L. Haga Siddaraju V. Boregowda Jacqueline Strivelli Donald G. Phinney
author_sort	Cori N. Booker
title	Transcriptional responses of skeletal stem/progenitor cells to hindlimb unloading and recovery correlate with localized but not systemic multi-systems impacts
title_short	Transcriptional responses of skeletal stem/progenitor cells to hindlimb unloading and recovery correlate with localized but not systemic multi-systems impacts
title_full	Transcriptional responses of skeletal stem/progenitor cells to hindlimb unloading and recovery correlate with localized but not systemic multi-systems impacts
title_fullStr	Transcriptional responses of skeletal stem/progenitor cells to hindlimb unloading and recovery correlate with localized but not systemic multi-systems impacts
title_full_unstemmed	Transcriptional responses of skeletal stem/progenitor cells to hindlimb unloading and recovery correlate with localized but not systemic multi-systems impacts
title_sort	transcriptional responses of skeletal stem/progenitor cells to hindlimb unloading and recovery correlate with localized but not systemic multi-systems impacts
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3c13a6b3b57648d89fc2e9a8526667c9
work_keys_str_mv	AT corinbooker transcriptionalresponsesofskeletalstemprogenitorcellstohindlimbunloadingandrecoverycorrelatewithlocalizedbutnotsystemicmultisystemsimpacts AT christopherlhaga transcriptionalresponsesofskeletalstemprogenitorcellstohindlimbunloadingandrecoverycorrelatewithlocalizedbutnotsystemicmultisystemsimpacts AT siddarajuvboregowda transcriptionalresponsesofskeletalstemprogenitorcellstohindlimbunloadingandrecoverycorrelatewithlocalizedbutnotsystemicmultisystemsimpacts AT jacquelinestrivelli transcriptionalresponsesofskeletalstemprogenitorcellstohindlimbunloadingandrecoverycorrelatewithlocalizedbutnotsystemicmultisystemsimpacts AT donaldgphinney transcriptionalresponsesofskeletalstemprogenitorcellstohindlimbunloadingandrecoverycorrelatewithlocalizedbutnotsystemicmultisystemsimpacts
_version_	1718407945509666816

Transcriptional responses of skeletal stem/progenitor cells to hindlimb unloading and recovery correlate with localized but not systemic multi-systems impacts

Ejemplares similares