TGFBI Expressed by Bone Marrow Niche Cells and Hematopoietic Stem and Progenitor Cells Regulates Hematopoiesis

Sofieke E Klamer, Yvonne L Dorland, Marion Kleijer, Dirk Geerts, William E Lento, C Ellen van der Schoot, Marieke von Lindern, Carlijn Voermans

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The interactions of hematopoietic stem and progenitor cells (HSPCs) with extracellular matrix (ECM) components and cells from the bone marrow (BM) microenvironment control their homeostasis. Regenerative BM conditions can induce expression of the ECM protein transforming growth factor beta-induced gene H3 (TGFBI or BIGH3) in murine HSPCs. In this study, we examined how increased or reduced TGFBI expression in human HSPCs and BM mesenchymal stromal cells (MSCs) affects HSPC maintenance, differentiation, and migration. HSPCs that overexpressed TGFBI showed accelerated megakaryopoiesis, whereas granulocyte differentiation and proliferation of granulocyte, erythrocyte, and monocyte cultures were reduced. In addition, both upregulation and downregulation of TGFBI expression impaired HSPC colony-forming capacity of HSPCs. Interestingly, the colony-forming capacity of HSPCs with reduced TGFBI levels was increased after long-term co-culture with MSCs, as measured by long-term culture-colony forming cell (LTC-CFC) formation. Moreover, TGFBI downregulation in HSPCs resulted in increased cobblestone area-forming cell (CAFC) frequency, a measure for hematopoietic stem cell (HSC) capacity. Concordantly, TGFBI upregulation in HSPCs resulted in a decrease of CAFC and LTC-CFC frequency. These results indicate that reduced TGFBI levels in HSPCs enhanced HSC maintenance, but only in the presence of MSCs. In addition, reduced levels of TGFBI in MSCs affected MSC/HSPC interaction, as observed by an increased migration of HSPCs under the stromal layer. In conclusion, tight regulation of TGFBI expression in the BM niche is essential for balanced HSPC proliferation and differentiation.

Original languageEnglish
Pages (from-to)1494-1506
Number of pages13
JournalStem cells and development
Issue number21
Publication statusPublished - 1 Nov 2018


  • Bone Marrow Cells/cytology
  • Cell Differentiation/genetics
  • Cell Line
  • Cell Movement/genetics
  • Cell Proliferation/genetics
  • Cobblestone Lissencephaly/genetics
  • Coculture Techniques
  • Extracellular Matrix Proteins/genetics
  • Flow Cytometry
  • Gene Expression Regulation, Developmental
  • Genetic Vectors
  • Hematopoiesis/genetics
  • Hematopoietic Stem Cells/cytology
  • Humans
  • Lentivirus/genetics
  • Mesenchymal Stem Cells/cytology
  • Stem Cells/cytology
  • Transforming Growth Factor beta/genetics

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