Specific Lineage-Priming of Bone Marrow Mesenchymal Stem Cells Provides the Molecular Framework for Their Plasticity

Abstract

Lineage-priming is a molecular model of stem cell (SC) differentiation in which proliferating SCs express a subset of genes associated to the differentiation pathways to which they can commit. This concept has been developed for hematopoietic SCs, but has been poorly studied for other SC populations. Because the differentiation potential of human bone marrow mesenchymal stem cells (BM MSCs) remains controversial, we have explored the theory of lineage-priming applied to these cells. We show that proliferating primary layers and clones of BM MSCs have precise priming to the osteoblastic (O), chondrocytic (C), adipocytic (A), and the vascular smooth muscle (V) lineages, but not to skeletal muscle, cardiac muscle, hematopoietic, hepatocytic, or neural lineages. Priming was shown both at the mRNA (300 transcripts were evaluated) and the protein level. In particular, the master transactivator proteins PPARG, RUNX2, and SOX9 were coexpressed before differentiation induction in all cells from incipient clones. We further show that MSCs cultured in the presence of inducers differentiate into the lineages for which they are primed. Our data point out to a number of signaling pathways that might be activated in proliferating MSCs and would be responsible for the differentiation and proliferation potential of these cells. Our results extend the notion of lineage-priming and provide the molecular framework for inter-A, -O, -C, -V plasticity of BM MSCs. Our data highlight the use of BM MSCs for the cell therapy of skeletal or vascular disorders, but provide a word of caution about their use in other clinical indications.

Stem Cells in the Human Breast

“…A similar interruption of TGF-b signaling in cancer may have the same effect. The fact that mammary epithelial stem cells seem to co-sort with cells of the myoepithelial lineage strongly supports the concept of so-called lineage-priming within the stem cell compartment (Delorme et al 2009). According to this, stem cells are not a "blank slate" in terms of expression of differentiationassociated genes but rather express subsets of genes associated with the differentiation pathways to which they commit.…”

Three-Dimensional In Vitro Tri-Culture Platform to Investigate Effects of Crosstalk Between Mesenchymal Stem Cells, Osteoblasts, and Adipocytes

“…We selected transcription factors for multiple MSC lineages, since their plasticity and level of lineage commitment are attributable to the simultaneous expression of these markers in their undifferentiated state that are progressively downregulated as the cells commit. 41 All lineage-specific transcription factors in these cells were affected to some extent by the co-and tri-culture settings. For example, AMA MSCs, the most distinct population of MSCs (Fig.…”

La biologie des cellules souchesmésenchymateuses d’origine humaine

“…En effet, l'observation qu'une population multiclonale donne plusieurs lignages peut s'expliquer par la coexistence de populations unipotentes, chacune pour un des quatre lignages. Il est ainsi attendu que les CSM puissent régénérer l'os et le cartilage lésés, ce qui a été largement démontré dans de nombreux modèles précliniques, dont celui de l'ostéogenèse imparfaite [20] [28]. Selon ce modèle, explicité en premier lieu pour les cellules souches hématopoïétiques (CSH), les cellules souches expriment, avant toute induction de différenciation vers leurs différents lignages, certains gènes caractéristiques de ces lignages, dont certains facteurs-clés de transcription.…”

“…Les chondrocytes de la plaque intermédiaire s'hypertrophient avant de se transformer en ostéoblastes. Des clones de CSM différenciés en A, O, C ou V peuvent donner des cellules de lignage mésenchymateux alternatif après modification des conditions de culture [27,28]. Compte tenu de l'homogénéité de la population cellulaire avant toute modification des conditions de culture, il est peu probable que ces résultats s'expliquent par la prolifération de CSM rési-duelles.…”

“…D'autres modèles peuvent s'appliquer, notamment ceux qui prennent en compte le phénomène de bruit dû aux variations stochastiques des niveaux d'expression de certains gènes ou réseaux de gènes [18]. Le phénomène de plasticité s'intègre bien au modèle de lineage priming des CSM [28]. Selon ce modèle, explicité en premier lieu pour les cellules souches hématopoïétiques (CSH), les cellules souches expriment, avant toute induction de différenciation vers leurs différents lignages, certains gènes caractéristiques de ces lignages, dont certains facteurs-clés de transcription.…”