TGFß-2 haploinsufficiency causes early death in mice with Marfan syndrome.

To assess the contribution of individual TGF-ß isoforms to aortopathy in Marfan syndrome (MFS), we quantified the survival and phenotypes of mice with a combined fibrillin1 (the gene defective in MFS) hypomorphic mutation and a TGF-ß1, 2, or 3 heterozygous null mutation. The loss of TGF-ß2, and only TGF-ß2, resulted in 80% of the double mutant animals dying earlier, by postnatal day 20, than MFS only mice. Death was not from thoracic aortic rupture, as observed in MFS mice, but was associated with hyperplastic aortic valve leaflets, aortic regurgitation, enlarged aortic root, increased heart weight, and impaired lung alveolar septation. Thus, there appears to be a relationship between loss of fibrillin1 and TGF-ß2 in the postnatal development of the heart, aorta and lungs.

Latent transforming growth factor ß binding protein 3 controls adipogenesis.

Transforming growth factor-beta (TGFß) is released from cells as part of a trimeric latent complex consisting of TGFß, the TGFß propeptides, and either a latent TGFß binding protein (LTBP) or glycoprotein-A repetitions predominant (GARP) protein. LTBP1 and 3 modulate latent TGFß function with respect to secretion, matrix localization, and activation and, therefore, are vital for the proper function of the cytokine in a number of tissues. TGFß modulates stem cell differentiation into adipocytes (adipogenesis), but the potential role of LTBPs in this process has not been studied. We observed that 72 h post adipogenesis initiation Ltbp1, 2, and 4 expression levels decrease by 74-84%, whereas Ltbp3 expression levels remain constant during adipogenesis. We found that LTBP3 silencing in C3H/10T1/2 cells reduced adipogenesis, as measured by the percentage of cells with lipid vesicles and the expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ). Lentiviral mediated expression of an Ltbp3 mRNA resistant to siRNA targeting rescued the phenotype, validating siRNA specificity. Knockdown (KD) of Ltbp3 expression in 3T3-L1, M2, and primary bone marrow stromal cells (BMSC) indicated a similar requirement for Ltbp3. Epididymal and inguinal white adipose tissue fat pad weights of Ltbp3-/- mice were reduced by 62% and 57%, respectively, compared to wild-type mice. Inhibition of adipogenic differentiation upon LTBP3 loss is mediated by TGFß, as TGFß neutralizing antibody and TGFß receptor I kinase blockade rescue the LTBP3 KD phenotype. These results indicate that LTBP3 has a TGFß-dependent function in adipogenesis both in vitro and possibly in vivo. SIGNIFICANCE: Understanding the control of mesenchymal stem cell fate is crucial for the potential use of these cells for regenerative medicine.