Convergence of TGFβ and BMP signaling in regulating human bone marrow stromal cell differentiation

Mona El-Safadi, Tasneem Shinwari, Sami Al-Malki, Muthurangan Manikandan, Amer Mahmood, Abdullah Aldahmash, Musaad Alfayez, Moustapha Kassem, Nehad M. Alajez*

*Corresponding author for this work

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Abstract

Targeting regulatory signaling pathways that control human bone marrow stromal (skeletal or mesenchymal) stem cell (hBMSC) differentiation and lineage fate determination is gaining momentum in the regenerative medicine field. Therefore, to identify the central regulatory mechanism of osteoblast differentiation of hBMSCs, the molecular phenotypes of two clonal hBMSC lines exhibiting opposite in vivo phenotypes, namely, bone forming (hBMSC +bone ) and non-bone forming (hBMSC −Bone ) cells, were studied. Global transcriptome analysis revealed significant downregulation of several TGFβ responsive genes, namely, TAGLN, TMP1, ACTA2, TGFβ2, SMAD6, SMAD9, BMP2, and BMP4 in hBMSC −Bone cells and upregulation on SERPINB2 and NOG. Transcriptomic data was associated with marked reduction in SMAD2 protein phosphorylation, which thereby implies the inactivation of TGFβ and BMP signaling in those cells. Concordantly, activation of TGFβ signaling in hBMSC −Bone cells using either recombinant TGFβ1 protein or knockdown of SERPINB2 TGFβ-responsive gene partially restored their osteoblastic differentiation potential. Similarly, the activation of BMP signaling using exogenous BMP4 or via siRNA-mediated knockdown of NOG partially restored the differentiation phenotype of hBMSC −Bone cells. Concordantly, recombinant NOG impaired ex vivo osteoblastic differentiation of hBMSC +Bone cells, which was associated with SERBINB2 upregulation. Our data suggests the existence of reciprocal relationship between TGFB and BMP signaling that regulates hBMSC lineage commitment and differentiation, whilst provide a plausible strategy for generating osteoblastic committed cells from hBMSCs for clinical applications.

Original languageEnglish
Article number4977
JournalScientific Reports
Volume9
Number of pages13
ISSN2045-2322
DOIs
Publication statusPublished - 21. Mar 2019

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Mesenchymal Stromal Cells
Cell Differentiation
Up-Regulation
Regenerative Medicine
Gene Expression Profiling
Cell Lineage
Osteoblasts
Recombinant Proteins
Small Interfering RNA
Down-Regulation
Proteins

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El-Safadi, M., Shinwari, T., Al-Malki, S., Manikandan, M., Mahmood, A., Aldahmash, A., ... Alajez, N. M. (2019). Convergence of TGFβ and BMP signaling in regulating human bone marrow stromal cell differentiation. Scientific Reports, 9, [4977]. https://doi.org/10.1038/s41598-019-41543-0
El-Safadi, Mona ; Shinwari, Tasneem ; Al-Malki, Sami ; Manikandan, Muthurangan ; Mahmood, Amer ; Aldahmash, Abdullah ; Alfayez, Musaad ; Kassem, Moustapha ; Alajez, Nehad M. / Convergence of TGFβ and BMP signaling in regulating human bone marrow stromal cell differentiation. In: Scientific Reports. 2019 ; Vol. 9.
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abstract = "Targeting regulatory signaling pathways that control human bone marrow stromal (skeletal or mesenchymal) stem cell (hBMSC) differentiation and lineage fate determination is gaining momentum in the regenerative medicine field. Therefore, to identify the central regulatory mechanism of osteoblast differentiation of hBMSCs, the molecular phenotypes of two clonal hBMSC lines exhibiting opposite in vivo phenotypes, namely, bone forming (hBMSC +bone ) and non-bone forming (hBMSC −Bone ) cells, were studied. Global transcriptome analysis revealed significant downregulation of several TGFβ responsive genes, namely, TAGLN, TMP1, ACTA2, TGFβ2, SMAD6, SMAD9, BMP2, and BMP4 in hBMSC −Bone cells and upregulation on SERPINB2 and NOG. Transcriptomic data was associated with marked reduction in SMAD2 protein phosphorylation, which thereby implies the inactivation of TGFβ and BMP signaling in those cells. Concordantly, activation of TGFβ signaling in hBMSC −Bone cells using either recombinant TGFβ1 protein or knockdown of SERPINB2 TGFβ-responsive gene partially restored their osteoblastic differentiation potential. Similarly, the activation of BMP signaling using exogenous BMP4 or via siRNA-mediated knockdown of NOG partially restored the differentiation phenotype of hBMSC −Bone cells. Concordantly, recombinant NOG impaired ex vivo osteoblastic differentiation of hBMSC +Bone cells, which was associated with SERBINB2 upregulation. Our data suggests the existence of reciprocal relationship between TGFB and BMP signaling that regulates hBMSC lineage commitment and differentiation, whilst provide a plausible strategy for generating osteoblastic committed cells from hBMSCs for clinical applications.",
author = "Mona El-Safadi and Tasneem Shinwari and Sami Al-Malki and Muthurangan Manikandan and Amer Mahmood and Abdullah Aldahmash and Musaad Alfayez and Moustapha Kassem and Alajez, {Nehad M.}",
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El-Safadi, M, Shinwari, T, Al-Malki, S, Manikandan, M, Mahmood, A, Aldahmash, A, Alfayez, M, Kassem, M & Alajez, NM 2019, 'Convergence of TGFβ and BMP signaling in regulating human bone marrow stromal cell differentiation', Scientific Reports, vol. 9, 4977. https://doi.org/10.1038/s41598-019-41543-0

Convergence of TGFβ and BMP signaling in regulating human bone marrow stromal cell differentiation. / El-Safadi, Mona; Shinwari, Tasneem; Al-Malki, Sami; Manikandan, Muthurangan; Mahmood, Amer; Aldahmash, Abdullah; Alfayez, Musaad; Kassem, Moustapha; Alajez, Nehad M.

In: Scientific Reports, Vol. 9, 4977, 21.03.2019.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Convergence of TGFβ and BMP signaling in regulating human bone marrow stromal cell differentiation

AU - El-Safadi, Mona

AU - Shinwari, Tasneem

AU - Al-Malki, Sami

AU - Manikandan, Muthurangan

AU - Mahmood, Amer

AU - Aldahmash, Abdullah

AU - Alfayez, Musaad

AU - Kassem, Moustapha

AU - Alajez, Nehad M.

PY - 2019/3/21

Y1 - 2019/3/21

N2 - Targeting regulatory signaling pathways that control human bone marrow stromal (skeletal or mesenchymal) stem cell (hBMSC) differentiation and lineage fate determination is gaining momentum in the regenerative medicine field. Therefore, to identify the central regulatory mechanism of osteoblast differentiation of hBMSCs, the molecular phenotypes of two clonal hBMSC lines exhibiting opposite in vivo phenotypes, namely, bone forming (hBMSC +bone ) and non-bone forming (hBMSC −Bone ) cells, were studied. Global transcriptome analysis revealed significant downregulation of several TGFβ responsive genes, namely, TAGLN, TMP1, ACTA2, TGFβ2, SMAD6, SMAD9, BMP2, and BMP4 in hBMSC −Bone cells and upregulation on SERPINB2 and NOG. Transcriptomic data was associated with marked reduction in SMAD2 protein phosphorylation, which thereby implies the inactivation of TGFβ and BMP signaling in those cells. Concordantly, activation of TGFβ signaling in hBMSC −Bone cells using either recombinant TGFβ1 protein or knockdown of SERPINB2 TGFβ-responsive gene partially restored their osteoblastic differentiation potential. Similarly, the activation of BMP signaling using exogenous BMP4 or via siRNA-mediated knockdown of NOG partially restored the differentiation phenotype of hBMSC −Bone cells. Concordantly, recombinant NOG impaired ex vivo osteoblastic differentiation of hBMSC +Bone cells, which was associated with SERBINB2 upregulation. Our data suggests the existence of reciprocal relationship between TGFB and BMP signaling that regulates hBMSC lineage commitment and differentiation, whilst provide a plausible strategy for generating osteoblastic committed cells from hBMSCs for clinical applications.

AB - Targeting regulatory signaling pathways that control human bone marrow stromal (skeletal or mesenchymal) stem cell (hBMSC) differentiation and lineage fate determination is gaining momentum in the regenerative medicine field. Therefore, to identify the central regulatory mechanism of osteoblast differentiation of hBMSCs, the molecular phenotypes of two clonal hBMSC lines exhibiting opposite in vivo phenotypes, namely, bone forming (hBMSC +bone ) and non-bone forming (hBMSC −Bone ) cells, were studied. Global transcriptome analysis revealed significant downregulation of several TGFβ responsive genes, namely, TAGLN, TMP1, ACTA2, TGFβ2, SMAD6, SMAD9, BMP2, and BMP4 in hBMSC −Bone cells and upregulation on SERPINB2 and NOG. Transcriptomic data was associated with marked reduction in SMAD2 protein phosphorylation, which thereby implies the inactivation of TGFβ and BMP signaling in those cells. Concordantly, activation of TGFβ signaling in hBMSC −Bone cells using either recombinant TGFβ1 protein or knockdown of SERPINB2 TGFβ-responsive gene partially restored their osteoblastic differentiation potential. Similarly, the activation of BMP signaling using exogenous BMP4 or via siRNA-mediated knockdown of NOG partially restored the differentiation phenotype of hBMSC −Bone cells. Concordantly, recombinant NOG impaired ex vivo osteoblastic differentiation of hBMSC +Bone cells, which was associated with SERBINB2 upregulation. Our data suggests the existence of reciprocal relationship between TGFB and BMP signaling that regulates hBMSC lineage commitment and differentiation, whilst provide a plausible strategy for generating osteoblastic committed cells from hBMSCs for clinical applications.

U2 - 10.1038/s41598-019-41543-0

DO - 10.1038/s41598-019-41543-0

M3 - Journal article

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 4977

ER -

El-Safadi M, Shinwari T, Al-Malki S, Manikandan M, Mahmood A, Aldahmash A et al. Convergence of TGFβ and BMP signaling in regulating human bone marrow stromal cell differentiation. Scientific Reports. 2019 Mar 21;9. 4977. https://doi.org/10.1038/s41598-019-41543-0