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Tallinn, Estonia

Jaager K.,Tallinn University of Technology | Jaager K.,Cellin Technologies LLC | Islam S.,Karolinska Institutet | Zajac P.,Karolinska Institutet | And 3 more authors.

Background: Tissue regeneration and recovery in the adult body depends on self-renewal and differentiation of stem and progenitor cells. Mesenchymal stem cells (MSCs) that have the ability to differentiate into various cell types, have been isolated from the stromal fraction of virtually all tissues. However, little is known about the true identity of MSCs. MSC populations exhibit great tissue-, location- and patient-specific variation in gene expression and are heterogeneous in cell composition. Methodology/Principal Findings: Our aim was to analyze the dynamics of differentiation of two closely related stromal cell types, adipose tissue-derived MSCs (AdMSCs) and dermal fibroblasts (FBs) along adipogenic, osteogenic and chondrogenic lineages using multiplex RNA-seq technology. We found that undifferentiated donor-matched AdMSCs and FBs are distinct populations that stay different upon differentiation into adipocytes, osteoblasts and chondrocytes. The changes in lineage-specific gene expression occur early in differentiation and persist over time in both AdMSCs and FBs. Further, AdMSCs and FBs exhibit similar dynamics of adipogenic and osteogenic differentiation but different dynamics of chondrogenic differentiation. Conclusions/Significance: Our findings suggest that stromal stem cells including AdMSCs and dermal FBs exploit different molecular mechanisms of differentiation to reach a common cell fate. The early mechanisms of differentiation are lineage-specific and are similar for adipogenic and osteogenic differentiation but are distinct for chondrogenic differentiation between AdMSCs and FBs. © 2012 Jääger et al. Source

Jaager K.,Tallinn University of Technology | Jaager K.,Cellin Technologies LLC | Neuman T.,Tallinn University of Technology | Neuman T.,Cellin Technologies LLC
Stem Cells and Development

Human dermal fibroblasts (FBs) express mesenchymal stem cell (MSC)-specific cell surface markers and differentiate into several cell types under appropriate conditions. Molecular mechanisms controlling the early stages of differentiation of dermal FBs and MSCs isolated from different sources have not been well studied. Here, we have analyzed the cell type-specific changes of adipose tissue-derived mesenchymal stem cells (AdMSCs) and dermal FBs in the process of differentiation into adipocytes and osteoblasts. Analysis of gene expression in the course of adipogenic differentiation of AdMSCs and FBs isolated from the same individuals revealed a time lag in the induction of adipogenesis-related genes in FBs compared with AdMSCs, a phenomenon not previously described. Further, preliminary evidence suggests that delayed adipogenesis of FBs is related to the delayed induction of preadipocyte transcription factor ZNF423 in FBs. These findings clearly show that AdMSCs and FBs have similar developmental potential but different molecular control mechanisms of initial stages of adipogenic differentiation. © Copyright 2011, Mary Ann Liebert, Inc. Source

Piirsoo A.,Protobios LLC | Piirsoo A.,Cellin Technologies LLC | Kasak L.,Protobios LLC | Kasak L.,Tallinn University of Technology | And 6 more authors.
Biochimica et Biophysica Acta - Molecular Cell Research

Observations that Glioma-associated transcription factors Gli1 and Gli2 (Gli1/2), executers of the Sonic Hedgehog (Shh) signaling pathway and targets of the Transforming Growth Factor β (TGF-β) signaling axis, are involved in numerous developmental and pathological processes unveil them as attractive pharmaceutical targets. Unc-51-like serine/threonine kinase Ulk3 has been suggested to play kinase activity dependent and independent roles in the control of Gli proteins in the context of the Shh signaling pathway. This study aimed at investigating whether the mechanism of generation of Gli1/2 transcriptional activators has similarities regardless of the signaling cascade evoking their activation. We also elucidate further the role of Ulk3 kinase in regulation of Gli1/2 proteins and examine SU6668 as an inhibitor of Ulk3 catalytic activity and a compound targeting Gli1/2 proteins in different cell-based experimental models. Here we demonstrate that Ulk3 is required not only for maintenance of basal levels of Gli1/2 proteins but also for TGF-β or Shh dependent activation of endogenous Gli1/2 proteins in human adipose tissue derived multipotent stromal cells (ASCs) and mouse immortalized progenitor cells, respectively. We show that cultured ASCs possess the functional Shh signaling axis and differentiate towards osteoblasts in response to Shh. Also, we demonstrate that similarly to Ulk3 RNAi, SU6668 prevents de novo expression of Gli1/2 proteins and antagonizes the Gli-dependent activation of the gene expression programs induced by either Shh or TGF-β. Our data suggest SU6668 as an efficient inhibitor of Ulk3 kinase allowing manipulation of the Gli-dependent transcriptional outcome. © 2014 The Authors. Source

Jaager K.,Tallinn University of Technology | Jaager K.,Cellin Technologies LLC | Fatkina A.,Cellin Technologies LLC | Velts A.,Cellin Technologies LLC | And 3 more authors.

Mesenchymal stem cells (MSCs) possess a multi-lineage differentiation capacity that makes them important players in the field of regenerative medicine. MSC populations derived from different tissues or donors have been shown to exhibit variable gene expression patterns. Further, it is widely acknowledged that MSC isolates are heterogeneous mixtures of cells at different developmental stages. However, the heterogeneity of expression of lineage regulators has not been linked to differentiation potential of different MSC populations towards mesenchymal lineages. Here, we analyzed variation of expression of differentiation markers across whole population and between single differentiating cells of multipotent stromal cell populations derived from adipose tissue (AdMSCs) and skin (FBs) of seven donors. The results of the analyses show that all cell populations exhibit similar differentiation potential towards adipocyte, osteoblast and chondrocyte lineages despite tissue type- and donor-specific variations of expression of differentiation-associated genes. Further, we detected variable expression of lineage regulators in individual differentiating cells. Together, our data indicate that single cells of stromal cell populations could use distinct molecular mechanisms to reach a common cell fate. © 2013 Elsevier B.V. Source

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