Dissecting the Hierarchy and Lineage of Mesenchymal Stem Cells Using Mouse Genetics as a Step toward Drug Discovery and Regenerative Medicine

Research output: Contribution to journalArticle

Abstract

The mesenchymal stem cell (MSC) is a type of tissue stem cell. In clinical studies, cultured MSCs have shown important therapeutic effects on diseases via both the reduction of neurological defects and the regulation of immune responses. However, in vivo MSC localization, function, and properties are poorly understood; therefore, the molecular understanding of MSC hierarchy is less advanced compared to hematopoietic stem cell hierarchy. Runt-related transcription factor 2 (Runx2) is an essential transcriptional regulator of osteoblast differentiation from MSCs. Runx2 deficiency in Paired-related homeobox 1 (Prrx1)-derived cells (Runx2Prrx1-/- mice) results in defective intramembranous ossification. Double-positive cells for Prrx1-GFP, and stem cell antigen-1 (Sca1) (Prrx1+Sca1+ cells) in the calvaria, express Runx2 at lower levels, and are more homogeneous and primitive compared with Prrx1+Sca1- cells. Our results suggest that osteoblast differentiation in vivo may begin at the Prrx1+Sca1+ MSC stage, with sequential progression to Prrx1+Sca1- cells, followed by Osterix+Prrx1-Sca1- osteoblast precursors, which eventually form mature α1(I)-collagen+ osteoblasts. This research will enable us to better understand the in vivo molecular biology features of MSCs, leading to their therapeutic applications for tissue repair and regeneration.

Original languageEnglish
Pages (from-to)867-871
Number of pages5
JournalYakugaku zasshi : Journal of the Pharmaceutical Society of Japan
Volume139
Issue number6
DOIs
Publication statusPublished - Jan 1 2019

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Regenerative Medicine
Homeobox Genes
Drug Discovery
Mesenchymal Stromal Cells
Stem Cells
Osteoblasts
Antigens
Therapeutic Uses
Hematopoietic Stem Cells
Osteogenesis
Skull
Regeneration
Molecular Biology
Transcription Factors
Collagen
Research

Keywords

  • hierarchy
  • mesenchymal stem cell
  • paired-related homeobox 1

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

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abstract = "The mesenchymal stem cell (MSC) is a type of tissue stem cell. In clinical studies, cultured MSCs have shown important therapeutic effects on diseases via both the reduction of neurological defects and the regulation of immune responses. However, in vivo MSC localization, function, and properties are poorly understood; therefore, the molecular understanding of MSC hierarchy is less advanced compared to hematopoietic stem cell hierarchy. Runt-related transcription factor 2 (Runx2) is an essential transcriptional regulator of osteoblast differentiation from MSCs. Runx2 deficiency in Paired-related homeobox 1 (Prrx1)-derived cells (Runx2Prrx1-/- mice) results in defective intramembranous ossification. Double-positive cells for Prrx1-GFP, and stem cell antigen-1 (Sca1) (Prrx1+Sca1+ cells) in the calvaria, express Runx2 at lower levels, and are more homogeneous and primitive compared with Prrx1+Sca1- cells. Our results suggest that osteoblast differentiation in vivo may begin at the Prrx1+Sca1+ MSC stage, with sequential progression to Prrx1+Sca1- cells, followed by Osterix+Prrx1-Sca1- osteoblast precursors, which eventually form mature α1(I)-collagen+ osteoblasts. This research will enable us to better understand the in vivo molecular biology features of MSCs, leading to their therapeutic applications for tissue repair and regeneration.",
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