Mesenchymal progenitor cells in intramuscular connective tissue development

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Mesenchymal progenitor cells in intramuscular connective tissue development Min Du, Ph.D. Professor and Endowed Chair Department of Animal Sciences Washington State University Pullman, WA

Beef Quality: marbling and tenderness Beef quality is mainly determined by marbling and tenderness. Marbling is the primary criterion for grading beef carcasses. Only carcasses with moderate to abundant marbling qualify for high quality grades.

Beef Quality: marbling and tenderness Beef tenderness is determined by: Myofibrillar effect: aging, stretching carcasses improves tenderness. Background toughness: connective tissue, mainly collagen and its cross linking. Both collagen content and cross linking increase as animals become older. Question: How to reduce collagen content and cross linking in muscle?

Tenderness remains a top problem for beef Collagen content and cross linking, two critical control points: How to reduce Fibroblasts synthesize collagen and other fibrotic proteins in connective tissue. fibroblasts? Fibroblasts secrete enzymes catalyzing collagen crosslinking. Collagen content Collagen cross linking

Tenderness remains a top problem for beef How to reduce fibroblasts? Fibroblasts are derived from mesenchymal multipotent cells, primarily during the early developmental stage. More importantly, fibroblasts and adipocytes share a common immediate progenitor cells, so called fibro/adipogenic cells (FAPs).

Myocytes 1 Myogenic progenitor cells Satellite cells Fibroblasts Stem cells in early embryos Fibro/adipogenic progenitor cells in fetuses 2 Adipocytes Resident fibro/adipogenic progenitor cells 1 2 In the stromal vascular fraction of mature muscle : Why do some stem cells become myogenic cells, while others become fibro/adipogenic cells? : Why do some progenitor cells become adipocytes, while others become fibrogenic cells?

Myocytes 1 Myogenic progenitor cells Satellite cells Fibroblasts Stem cells in early embryos Fibro/adipogenic progenitor cells In fetuses 2 Adipocytes Resident fibro/adipogenic progenitor cells In the stromal vascular fraction of mature muscle The mechanisms regulating mesenchymal progenitor cell commitment to myogenesis, adipogenesis and fibrogenesis are poorly defined, especially in livestock.

Myocytes 1 Myogenic progenitor cells Satellite cells Fibroblasts Stem cells in early embryos Fibro/adipogenic progenitor cells In fetuses 2 Adipocytes Resident fibro/adipogenic progenitor cells In the stromal vascular fraction of mature muscle Tumor necrosis factor (TGF) signaling pathway and Zfp423 transcription factor appear to have critical roles in determining progenitor commitments to either adipogenic or fibrogenic lineages.

Transforming growth factor (TGF) and fibrogenesis TGF TGF is a major signaling pathway promoting fibrogenesis. TGF TGF TGF TGF RII RI T204 RII RI GS Kinase Kinase Kinase Kinase Smad 2 S465 S467 Smad 3 S422 S424 TGF signaling is enhanced by inflammation and other factors. Obesity is known to induce inflammation and TGF signaling. Fetal stage is critical for fibrogenesis. P P Smad 3 P P P Smad 3 P Smad7 Collagen Cross linking enzymes AAAAA

Experimental design Objective: Thus, a maternal obesity sheep model was used to assess the role of TGF β signaling on fibrogenesis during early development. Animals: Non pregnant ewes were assigned to a control diet (Con, fed 100% of NRC nutrient recommendations, n = 6) or obesogenic diet (OB) fed 150% of NRC recommendations, n = 6) from 60 days before conception. Fetal semitendinosus (St) muscle was sampled at 135 days of gestation (term 148 days). Methods: Histochemical analyses, Hydroxyproline assay, Real time PCR, Western blot analyses, Electrophoretic mobility shift assay (EMSA). Huang et al., AJP Endocrinology and Metabolism 298:1254 1260, 2010

Enhanced tumor necrosis factor (TNF) expression in OB fetal muscle Arbitary Unit 1.5 1 0.5 0 Con OB 1.8 1.4 1 0.6 0.2 Con OB NF - B p65 GAPDH TNF : A marker of systemic inflammation. NF B: A major inflammatory signaling. Xu et al., Endocrinology, 2010, 151: 380.

Transforming growth factor (TGF) content increased in OB fetal muscle TGF TGF TGF TGF TGF RII RI T204 RII RI GS Kinase Kinase Kinase Kinase Smad 2 Smad 3 S465 S467 S422 S424 TGFβ Precursor Con OB Con OB Tubulin P TGFβ Precursor 3.5 3 2.5 2 1.5 1 0.5 P P Smad 3 P P Smad 3 P Smad7 Collagen Cross linking enzymes AAAAA 0 Con OB Smad binding element (SBE) Huang et al., AJP Endocrinology and Metabolism 298:1254 1260, 2010

Binding to Smad responsive element was increased in OB fetal muscle P32 labeled Smad binding elements Con OB Shift band Free probe Relative SBE shift 2.5 2 1.5 1 0.5 0 Con OB Huang et al., AJP Endocrinology and Metabolism 298:1254 1260, 2010

Expression of Smad7 was enhanced in OB fetal muscle TGF TGF TGF TGF TGF RII RI T204 RII RI GS Kinase Kinase Kinase Kinase Smad 2 S465 S467 Smad 3 S422 S424 P Smad 7 6 5 4 3 2 1 0 P < 0.05 Con OB P P Smad 3 P P Smad 3 P Smad7 Collagen Cross linking enzymes AAAAA Huang et al., AJP Endocrinology and Metabolism 298:1254 1260, 2010

Expression of TGF target genes was enhanced (Connective tissue content) Procollagen Type I 3.5 3 2.5 2 1.5 1 0.5 0 P = 0.08 Con & OB Fibronectin 4.0 3.0 2.0 1.0 0.0 P < 0.05 Con OB Procollagen: Precursor of collagen. Fibronectin: Extracellular matrix glycoprotein. Huang et al., AJP Endocrinology and Metabolism 298:1254 1260, 2010

Expression of TGF target genes was enhanced (Collagen cross linking) P4HA 2.5 2 1.5 1 0.5 0 P = 0.05 Con & OB LH2b 4 3 2 1 0 P < 0.05 Con OB Lysyl oxidase 6 5 4 3 2 1 0 P < 0.05 Con OB P4HA: prolyl 4 hydroxylase, formation of hydroxyproline. LH2b: lysyl hydroxylase 2b, collagen cross linking. Lysyl oxidase: amine oxidase, collagen cross linking. Huang et al., AJP Endocrinology and Metabolism 298:1254 1260, 2010

Transforming growth factor (TGF) and fibrogenesis CON x100 x400 Collagen area/view area (%) 40 30 20 10 0 Con OB OB Collagen/dry muscle weight (mg/g) 160 120 80 40 Con OB Huang et al., AJP Endocrinology and Metabolism 298:1254 1260, 2010

Con OB Sheep fetal muscle at 135 dg when skeletal muscle matures (term day 148 gestation). Xu et al., Endocrinology, 2010, 151: 380.

Myocytes Satellite cells 1 Myogenic progenitor cells Fibroblasts Stem cells in early embryos Fibro/adipogenic progenitor cells In fetuses 2 Adipocytes Resident fibro/adipogenic progenitor cells In the stromal vascular fraction of mature muscle It appears that the fibro/adipogenic pathway was enhanced in fetal muscle due to obesity and over nutrition in early development Control point 1.

Myocytes Satellite cells 1 Myogenic progenitor cells Fibroblasts Stem cells in early embryos Fibro/adipogenic progenitor cells In fetuses 2 Adipocytes Resident fibro/adipogenic progenitor cells In the stromal vascular fraction of mature muscle To further study mechanisms regulating lineage commitments of mesenchymal stem cells and progenitor cells, we used Wagyu and Angus cattle.

Wagyu cattle are known for its extremely high marbling Wagyu cattle are known for their extremely high marbling. Due to their similarities in growth characteristics, but sufficient difference in marbling, Wagyu and Angus cattle are frequently compared. We sampled the Sternomandibularis muscle for analyses.

Wagyu muscle have enhanced adipogenesis Arbitrary units 2.5 2.0 1.5 1.0 0.5 0.0 P = 0.2864 CEBPβ Arbitrary units 4.0 3.0 2.0 1.0 0.0 CEBPα Arbitrary units 5.0 4.0 3.0 2.0 1.0 0.0 PPARγ Arbitrary units 2.5 2.0 1.5 1.0 0.5 0.0 Zfp423 % of ether extract 4.0 3.0 2.0 1.0 0.0 Intramuscular fat (IMF) Duarte et al., J. Anim. Sci., 2013, 91: 2938

Wagyu cattle have higher fibrogenesis Arbitrary units 4.0 3.0 2.0 1.0 0.0 TGFβ Arbitrary units 3.0 2.0 1.0 0.0 FIBRONECTIN Fibronectin Arbitrary units 2.5 2.0 1.5 1.0 0.5 0.0 FGF-2 Arbitrary units 2.0 1.5 1.0 0.5 0.0 FGFR FGFr Duarte et al., J. Anim. Sci., 2013, 91: 2938

Wagyu cattle are higher collagen content Collagen mrna expression (arbitrary units) 4.0 3.0 2.0 1.0 0.0 Collagen COL I I Collagen COL III III mg/g of muscle 4.0 3.0 2.0 1.0 0.0 Collagen content Duarte et al., J. Anim. Sci., 2013, 91: 2938

Wagyu cattle are higher collagen content 100x 200x 400x Angus Wagyu Duarte et al., J. Anim. Sci., 2013, 91: 2938

Wagyu have decreased myogenic pathway Frequency 150 100 50 0 Angus Wagyu 20 45 70 95 120 Diameter (µm) Diameter (µm) 100 80 60 40 20 0 Angus Breeds Wagyu Angus Wagyu Attenuated fetal myogenesis forms less muscle fibers. The larger muscle fiber diameter in Wagyu despite less muscle mass shows less muscle fiber numbers, indicating attenuated myogenesis during early development. Duarte et al., J. Anim. Sci., 2013, 91: 2938

Myocytes Satellite cells 1 Myogenic progenitor cells Fibroblasts Stem cells in early embryos Fibro/adipogenic progenitor cells In fetuses 2 Adipocytes Resident fibro/adipogenic progenitor cells It appears that both fibro/adipogenic pathway (1 st question) and adipogenic differentiation (2 nd question) are enhanced in Wagyu, which we are exploring. Our current studies focus on Zfp423. In the stromal vascular fraction of mature muscle

Zfp423 in adipogenesis of fibro/adipogenic progenitor cells Key question 2: what determines the lineage commitment of fibro/adipogenic cells (FAPs)? Zinc finger protein (Zfp) 423 is a newly identified transcription factor regulating adipogenic commitment of FAPs, which induces adipogenic differentiation and reduces fibrogenesis. Zfp423 PPAR FAPs Pre Adipocytes Adipocytes Adipogenic commitment Adipogenic differentiation

What is Zfp423? We hypothesized that Zfp423 is critical for adipogenic differentiation of intramuscular fibro/adipogenic progenitor cells. Zfp423 is correlated with enhanced adipogenesis and reduced fibrogenesis in beef cattle.

Methods Animal: The Sternocleidomastoid muscle was sampled from the carcass of an Angus heifer (20 months of age) immediately after slaughter. Stromal vascular cells were separated, immortalized by over expression of telomerase, and cloned. Three clones with high adipogenic and low adipogenic potential respectively were selected.

Zfp423 in adipogenesis of fibro/adipogenic progenitor cells A High adipogenic C Low adipogenic B Arbitrary units 2.5 2 1.5 1 0.5 D 0 High adipogenic Low adipogenic Huang et al., PLOS one, 2012, 7: e47496

mrna expression of Zfp423 and other genes 5.0 4.0 Before differentiation Arbitrary units 3.0 2.0 1.0 & & 0.0 9.0 Zfp423 PPARr PPARγ C/EBPa C/EBPα C/EBPb C/EBP Fibronectin TGF TGFb CollagenI CollagenIII Adipogenic differentiation for 13 days Low adipogenic High adipogenic Arbitrary units 6.0 3.0 & & 0.0 Zfp423 PPARr PPARγ C/EBPa C/EBPα C/EBPb C/EBP Fibronectin TGF TGFb CollagenI CollagenIII P < 0.05; & P < 0.10. Huang et al., PLOS one, 2012, 7: e47496

TGF signaling was higher in Low Adipogenic Cells Low adipogenic High adipogenic Low adipogenic High adipogenic TGF Tubulin TGF Tubulin Arbitrary units 2 1.6 1.2 0.8 0.4 & Arbitrary units 4.0 3.0 2.0 1.0 0 Low adipogenic High adipogenic 0.0 Low adipogenic High adipogenic Before adipogenic differentiation After adipogenic differentiation Huang et al., PLOS one, 2012, 7: e47496

Zfp423 over expression in low adipogenic cells enhances their adipogenic differentiation Arbitrary units 4 3.5 3 2.5 2 1.5 1 0.5 0 a c a bc a b Adipogenic NA Zfp423 transfection a b a ab bc c Non adipogenic NA GFP transfection Zfp423 C/EBPa C/EBP C/EBPb C/EBP PPARr PPAR Fibronectin TGFb TGF a ab a b b a ab b b a ab b (Bars marked with different letter differ, n =3.) Huang et al., PLOS one, 2012, 7: e47496

Zfp423 over expression in low adipogenic cells enhances their adipogenic differentiation TGF (Bars marked with different letter differ, n =3.) Huang et al., PLOS one, 2012, 7: e47496

Zfp423 in adipogenesis of fibro/adipogenic progenitor cells High adipogenic Low adipogenic Low adipogenic + Zfp423 Low adipogenic + egfp Low adipogenic High adipogenic High adipogenic + shzfp423 High adipogenic + GFP Huang et al., PLOS one, 2012, 7: e47496

Why does Zfp423 express at a higher level in high adipogenic cells? Both high and low adipogenic cells are from the same bovine animal. They have identical genetic composition. The difference in their adipogenic and fibrogenic differentiation should be due to epigenetic modifications. Because these cells have been immortalized and cloned, only stable epigenetic modifications, or DNA methylation, is expected to maintain.

Zfp423 promotor contains rich GC sites, and higher methylation in low compared to high adipogenic cells ATG Arbitrary units 5 4 3 2 1 Low adipogenic High adipogenic 0 TGF TGF b Zfp423 Methylated DNA immunoprecipitation (MeDIP) was used to measure the DNA methylation of Zfp423 promoter. Huang et al., PLOS one, 2012, 7: e47496

Zfp423 in adipogenesis of fibro/adipogenic progenitor cells Why do TGF and Zfp423 expression differ between low and high adipogenic cells? DNA methylation is a stable epigenetic modification which inhibits gene expression, determining cell phenotypes. TGF DNA methylation was higher, while Zfp423 DNA methylation was lower in low adipogenic cells, consistent with higher adipogenic and low fibrogenic differentiation of FAPs. Huang et al., PLOS one, 2012, 7: e47496

What regulates Zfp423 expression? We hypothesized that epigenetic modifications have key roles in regulating Zfp423 expression. Epigenetic modifications are mainly referring to DNA methylation and histone modifications. Histone modifications include histone methylation and acetylation, and others.

What regulates Zfp423 expression? Polycomb repressive complex 2 (PGC2) catalyzes repressive histone modifications, H3K27me3. Trithorax group proteins (TrxG) catalyze permissive histone modifications, H3K4me3. Both H3K27me3 and H3K4me3 co exist in key developmental genes, forming bivalent status. Lack of stimulation, repressive histone modifications convert to DNA methylation for permanent silencing.

Zfp423 promoter has a bivalent status A B Sect 1 Sect 2 Sect 3 Sect 4 Yang et al., Diabetes, 2013, 62:3727

Maternal obesity enhances Zfp423 expression in fetal tissue via inducing epigenetic changes To test the role of epigenetic changes in the regulation of Zfp423 expression, we used a dietinduced obesity pregnant mouse model. Female mice were fed either a control diet (Con) or an obesogenic diet (OB) for two months to induce obesity. Fetal mice at E14.5 were collected for analyses, when early adipose development has initiated.

DNA methylation was lower in Zfp423 of fetal tissue of obese mothers Sec1 Sec 2 Sec3 Sec4 Con OB CON vs. OB: 30.0% vs. 16.9% 38.0% vs. 21.0% 4.4% vs. 2.1% 0.4% vs. 0.0% Yang et al., Diabetes, 2013, 62:3727

Inhibitory histone modification, H3K27me3 is lower, and permissive modification, H3K4me3, is higher in OB Con OB IP Input IgG IP Input IgG H3K27me3 H3K4me3 Percent of input (%) 10.00 8.00 6.00 4.00 2.00 H3K27me3 Percent of input (%) 6.0 5.0 4.0 3.0 2.0 1.0 H3K4me3 0.00 Con OB 0.0 Con OB Yang et al., Diabetes, 2013, 62:3727

Inhibitory histone modification, H3K27me3 is lower, and permissive modification, H3K4me3, is higher in OB Con OB Zfp423 β-actin Zfp423 protein content (Arbitrary Unit) 1.2 1 0.8 0.6 0.4 0.2 0 Con HFD OB Yang et al., Diabetes, 2013, 62:3727

Proposed mechanism linking maternal obesity to epigenetic modifications in the Zfp423 promoter Normal pregnancy Maternal obesity PRC2 PRC2 PRC2 Zfp423 PRC2 Zfp423 AC AC AC Zfp423 promoter Zfp423 promoter AC H3K27me3 Methylated CpG Unmethylated CpG Acetylation

Myocytes 1 Myogenic progenitor cells Satellite cells Fibroblasts Stem cells in early embryos Fibro/adipogenic progenitor cells In fetuses 2 Adipocytes Resident fibro/adipogenic progenitor cells In the stromal vascular fraction of mature muscle In summary, there are two major control points for reducing intramuscular fibrogenesis: Stem cells to either myogenic or FAP lineage. FAPs to either adipogenic or fibrogenic lineage.

Mechanisms regulating mesenchymal progenitor cell differentiation Genetic, nutritional and other factors cell signaling pathways Adipocytes Multipotent cells Epigenetic changes in progenitor cells Muscle cells Fibroblasts

What controls mesenchymal progenitor cell differentiation? Critical questions. If we know these answers, We can: Improve lean/fat ratio and production efficiency. Reduces connective deposition and increase tenderness of beef. Enhance intramuscular adipogenesis and marbling.

Funding support:

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