Effect of miR-204&211 and RUNX2 control on the fate of human mesenchymal stromal cells

Benedetto Sacchetti, Alessandro Fatica, Melissa Sorci, Antonio Sorrentino, Michele Signore, Annamaria Cerio, Federica Felicetti, Alessandra De Feo, Elvira Pelosi, Alessandra Caré, Edoardo Pescarmona, Jan Oxholm Gordeladze, Mauro Valtieri

Research output: Contribution to journalArticle

Abstract

MiR-204 and 211 enforced expression in murine mesenchymal stromal cells (MSCs) has been shown to induce adipogenesis and impair osteogenesis, through RUNX2 down-modulation. This mechanism has been suggested to play a role in osteoporosis associated with obesity. However, two further fundamental MSC functions, chondrogenesis and hematopoietic supporting activity, have not yet been explored. To this end, we transduced, by a lenti-viral vector, miR-204 and 211 in a model primary human MSC line, opportunely chosen among our MSC collection for displaying all properties of canonical bone marrow MSCs, except adipogenesis. Enforced expression of miR-204&211 in these cells, rescued adipogenesis, and inhibited osteogenesis, as previously reported in murine MSCs, but, surprisingly, also damaged cartilage formation and hematopoietic supporting activity, which were never explored before. RUNX2 has been previously indicated as the target of miR-204&211, whose down modulation is responsible for the switch from osteogenesis to adipogenesis. However, the additional disruption of chondrogenesis and hematopoietic supporting activity, which we report here, might depend on diverse miR-204&211 targets. To investigate this hypothesis, permanent RUNX2 knock-down was performed. Sh-RUNX2 fully reproduced the phenotypes induced by miR-204&211, confirming that RUNX2 down modulation is the major event leading to the reported functional modification on our MSCs. It seems thus apparent that RUNX2, a recognized master gene for osteogenesis, might rule all four MSC commitment and differentiation processes. Hence, the formerly reported role of miR204&211 and RUNX2 in osteoporosis and obesity, coupled with our novel observation showing inhibition of cartilage differentiation and hematopoietic support, strikingly resemble the clinical traits of metabolic syndrome, where osteoarthritis, osteoporosis, anaemia and obesity occur together. Our observations, corroborating and extending previous observations, suggest that miR-204&211-RUNX2 axis in human MSCs is possibly involved in the pathogenesis of this rapidly growing disease in industrialized countries, for possible therapeutic intervention to regenerate former homeostasis.

Original languageEnglish
Pages (from-to)2
JournalRegenerative Medicine Research
Volume5
DOIs
Publication statusPublished - 2017

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Mesenchymal Stromal Cells
Modulation
Cartilage
Adipogenesis
Cells
Osteogenesis
Bone
Osteoporosis
Chondrogenesis
Genes
Switches
Obesity
Developed Countries
Osteoarthritis
Anemia
Cell Differentiation
Homeostasis
Observation
Phenotype
Cell Line

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Effect of miR-204&211 and RUNX2 control on the fate of human mesenchymal stromal cells. / Sacchetti, Benedetto; Fatica, Alessandro; Sorci, Melissa; Sorrentino, Antonio; Signore, Michele; Cerio, Annamaria; Felicetti, Federica; Feo, Alessandra De; Pelosi, Elvira; Caré, Alessandra; Pescarmona, Edoardo; Gordeladze, Jan Oxholm; Valtieri, Mauro.

In: Regenerative Medicine Research, Vol. 5, 2017, p. 2.

Research output: Contribution to journalArticle

Sacchetti, Benedetto ; Fatica, Alessandro ; Sorci, Melissa ; Sorrentino, Antonio ; Signore, Michele ; Cerio, Annamaria ; Felicetti, Federica ; Feo, Alessandra De ; Pelosi, Elvira ; Caré, Alessandra ; Pescarmona, Edoardo ; Gordeladze, Jan Oxholm ; Valtieri, Mauro. / Effect of miR-204&211 and RUNX2 control on the fate of human mesenchymal stromal cells. In: Regenerative Medicine Research. 2017 ; Vol. 5. pp. 2.
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AU - Sacchetti, Benedetto

AU - Fatica, Alessandro

AU - Sorci, Melissa

AU - Sorrentino, Antonio

AU - Signore, Michele

AU - Cerio, Annamaria

AU - Felicetti, Federica

AU - Feo, Alessandra De

AU - Pelosi, Elvira

AU - Caré, Alessandra

AU - Pescarmona, Edoardo

AU - Gordeladze, Jan Oxholm

AU - Valtieri, Mauro

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PY - 2017

Y1 - 2017

N2 - MiR-204 and 211 enforced expression in murine mesenchymal stromal cells (MSCs) has been shown to induce adipogenesis and impair osteogenesis, through RUNX2 down-modulation. This mechanism has been suggested to play a role in osteoporosis associated with obesity. However, two further fundamental MSC functions, chondrogenesis and hematopoietic supporting activity, have not yet been explored. To this end, we transduced, by a lenti-viral vector, miR-204 and 211 in a model primary human MSC line, opportunely chosen among our MSC collection for displaying all properties of canonical bone marrow MSCs, except adipogenesis. Enforced expression of miR-204&211 in these cells, rescued adipogenesis, and inhibited osteogenesis, as previously reported in murine MSCs, but, surprisingly, also damaged cartilage formation and hematopoietic supporting activity, which were never explored before. RUNX2 has been previously indicated as the target of miR-204&211, whose down modulation is responsible for the switch from osteogenesis to adipogenesis. However, the additional disruption of chondrogenesis and hematopoietic supporting activity, which we report here, might depend on diverse miR-204&211 targets. To investigate this hypothesis, permanent RUNX2 knock-down was performed. Sh-RUNX2 fully reproduced the phenotypes induced by miR-204&211, confirming that RUNX2 down modulation is the major event leading to the reported functional modification on our MSCs. It seems thus apparent that RUNX2, a recognized master gene for osteogenesis, might rule all four MSC commitment and differentiation processes. Hence, the formerly reported role of miR204&211 and RUNX2 in osteoporosis and obesity, coupled with our novel observation showing inhibition of cartilage differentiation and hematopoietic support, strikingly resemble the clinical traits of metabolic syndrome, where osteoarthritis, osteoporosis, anaemia and obesity occur together. Our observations, corroborating and extending previous observations, suggest that miR-204&211-RUNX2 axis in human MSCs is possibly involved in the pathogenesis of this rapidly growing disease in industrialized countries, for possible therapeutic intervention to regenerate former homeostasis.

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