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Supporting Information Supporting Information Higgins et al. 10.1073/pnas.1309970110 Fig. S1. Extracellular matrix and transcription factors in the human dermal papilla. (A) Versican (green), an extracellular matrix protein, is localized to the dermal papilla and sheath of human scalp hair follicles. (B) The transcription factor MZF1 (green) is observed within both the dermal papilla and the surrounding matrix of the follicle. (C) LEF1 (red) a key transcription factor in the Wnt signaling pathway is observed within a heterogeneous population of dermal papilla cells. (D) MEF2C (green), a transcription factor expressed within the dermal papilla and sheath of the follicle. Versican, MZF1, LEF1, and MEF2C were all identified as being present within intact dermal papilla whereas expression levels in these genes decreased after perturbation by 2D culture. (Scale bars: 100 μm.) Higgins et al. www.pnas.org/cgi/content/short/1309970110 1of11 Fig. S2. Induced hair follicles at 5 d and 6 wk post grafting. (A) Five days after grafting spheroids, we were able to identify spheroids by staining for alkaline phosphatase (purple); however, at this early time point, changes in the epidermis were not visible. (B) In several instances, different spheroids (arrows) were starting to merge together. (C and D) After 6 wk, we were able to detect quite immature hair follicles within some grafts, visualized using hematoxylin/eosin staining. (E) In other grafts, we could detect cysts (E) with associated dermal papilla, where hair follicles had started to form. (F and G) In several grafts, we detected more mature follicles after 6 wk, complete with inner root sheaths and hair shafts. (H) Induced hair follicles were often clustered in close proximity to each other. Higgins et al. www.pnas.org/cgi/content/short/1309970110 2of11 Fig. S3. Real-time PCR validation of microarray data. Genes grouped in territories T1–T4 within GEDI were analyzed by semiquantitative real-time PCR. Comparisons were made between intact papilla (F), cells at various stages in culture (p0, p1, p3, p5), and spheroids established at p3 (S). Scale bars were based on SD from the mean of three technical replicates. The t tests were performed on pairwise comparisons: F versus p3, and p3 versus S, with the resultant P value indicated on the graph if changes were significant. Higgins et al. www.pnas.org/cgi/content/short/1309970110 3of11 Fig. S4. Immunofluorescence analysis of proteins in territories T1 and T3. (A) Periostin (POSTN) (identified in T1) was highly expressed in all cells in 2D culture whereas, in spheroid cultures (B), expression was restricted to cells within the outer layer of the spheroid. Hyaluronan synthase 2 (HAS2) (identified in T1) was present in 2D cell cultures (C), but virtually absent in 3D spheroids (D). Bone morphogenetic protein 2 (BMP2) (in territory T3), in 2D cultures (E) was barely detectable whereas, in 3D culture (F), BMP2 was expressed by a large percentage of cells within the spheroid. Secreted frizzled receptor protein 4 (SFRP4) (in territory T3) was absent in 2D cultures (G), but was expressed at high levels in dermal spheroids (H). Matrix gla protein (MGP) (in territory T3) was barely detectable in 2D culture conditions (I) whereas, in spheroids (J), several cells expressed the protein. Alpha-2-macroglobulin (A2M) was present in 2D dermal papilla cell cultures (K), but, in 3D spheroids, levels were extremely high (L), consistent with its presence in territory T3. Higgins et al. www.pnas.org/cgi/content/short/1309970110 4of11 Fig. S5. Protein class analysis of transcripts restored in spheres due to an increase in expression as shown in T3. Panther algorithm analysis of protein classes restored by assembly of cells in 3D spheres. Pathways significantly over- or underrepresented (P > 0.05) within this list comparative to representation within the genome. Pathways are plotted with representation (%) on the left x axis, and their respective P value on the right x axis. Classes, including extracellular matrix, and signaling molecules are particularly overrepresented within spheres compared with representation of those terms within the Homo sapien genome. Table S1. Follicles induced after tissue recombination containing intact papillae or papilla cell slurries No. placed in No. of follicles Donor no. graft observed % inductivity D1 9 intact papillae 8 88.9 D2 7 intact papillae 1 14.3 D3 100,000 cells 0 0 D4 100,000 cells 0 0 D4 100,000 cells 0 0 Higgins et al. www.pnas.org/cgi/content/short/1309970110 5of11 Table S2. Selected transcripts significantly and differentially regulated between intact dermal papilla and cells at p0 Affymetrix ID FC (p0 vs. Intact DP) Gene symbol Affymetrix ID FC (p0 vs. Intact DP) Gene symbol 218468_s_at 415.9 GREM1 221685_s_at 35.1 CCDC99 218469_at 296.4 GREM1 230730_at 35.0 SGCD 228367_at 185.0 ALPK2 1555778_a_at 33.9 POSTN 204475_at 179.9 MMP1 218542_at 33.7 CEP55 222608_s_at 89.0 ANLN 204825_at 33.2 MELK 203889_at 82.3 SCG5 203939_at 33.1 NT5E 206432_at 82.3 HAS2 228729_at 32.4 CCNB1 230372_at 81.5 HAS2 204092_s_at 32.4 AURKA 209773_s_at 65.5 RRM2 207165_at 32.2 HMMR 201109_s_at 58.6 THBS1 223734_at 31.7 OSAP 214710_s_at 52.0 CCNB1 228602_at 31.6 SGCD 235086_at 51.6 THBS1 209016_s_at 31.2 KRT7 225285_at 51.5 BCAT1 202952_s_at 31.2 ADAM12 219654_at 50.7 PTPLA 210052_s_at 30.9 TPX2 226103_at 49.6 NEXN 204256_at 30.8 ELOVL6 222379_at 49.5 KCNE4 217678_at 30.8 SLC7A11 201467_s_at 48.9 NQO1 224663_s_at 30.5 CFL2 226517_at 47.8 BCAT1 226099_at 30.4 ELL2 235004_at 47.4 RBM24 206632_s_at 30.3 APOBEC3B 227399_at 45.4 VGLL3 228033_at 30.1 E2F7 219148_at 44.9 PBK 206157_at 30.1 PTX3 203764_at 44.0 DLG7 205339_at 29.9 STIL 239537_at 43.9 ST8SIA2 210519_s_at 29.9 NQO1 205132_at 43.5 ACTC1 213906_at 29.5 MYBL1 218888_s_at 43.0 NETO2 225687_at 29.2 FAM83D 219926_at 42.8 POPDC3 204932_at 29.1 TNFRSF11B 203789_s_at 40.6 SEMA3C 219918_s_at 28.1 ASPM 208079_s_at 40.3 AURKA 219619_at 27.9 DIRAS2 239336_at 40.0 THBS1 201951_at 27.8 ALCAM 201110_s_at 38.5 THBS1 203819_s_at 27.4 IGF2BP3 209758_s_at 38.3 MFAP5 219308_s_at 27.3 AK5 213068_at 37.7 DPT 213764_s_at 27.0 MFAP5 212681_at 37.5 EPB41L3 235318_at 26.9 FBN1 206307_s_at 36.7 FOXD1 203820_s_at 26.9 IGF2BP3 222774_s_at 36.3 NETO2 214702_at 26.7 FN1 212590_at 36.1 RRAS2 212472_at 26.6 MICAL2 209288_s_at 36.1 CDC42EP3 227870_at 26.0 NOPE 201108_s_at 35.9 THBS1 218009_s_at 25.6 PRC1 221029_s_at 35.8 WNT5B 222958_s_at 25.3 DEPDC1 213880_at 35.4 LGR5 204162_at 25.1 NDC80 205430_at −38.6 BMP5 203549_s_at −77.9 LPL 205638_at −38.6 BAI3 218353_at −79.2 RGS5 213921_at −39.4 SST 237466_s_at −79.4 HHIP 229947_at −40.7 PI15 219764_at −80.4 FZD10 236262_at −41.0 MMRN2 203477_at −81.1 COL15A1 209170_s_at −41.9 GPM6B 217757_at −83.4 A2M 205350_at −42.3 CRABP1 202036_s_at −85.6 SFRP1 1554012_at −43.5 RSPO2 203699_s_at −86.7 DIO2 228237_at −44.8 PAPPA2 208792_s_at −87.7 CLU 207242_s_at −45.6 GRIK1 227874_at −88.1 EMCN 219407_s_at −45.9 LAMC3 216834_at −88.6 RGS1 228067_at −47.0 C2orf55 202037_s_at −89.2 SFRP1 235182_at −47.5 C20orf82 223122_s_at −91.2 SFRP2 205206_at −47.7 KAL1 215271_at −92.0 TNN 223836_at −47.8 FGFBP2 216921_s_at −99.6 KRT35 209047_at −48.8 AQP1 217028_at −100.0 CXCR4 204249_s_at −49.0 LMO2 230418_s_at −101.0 GALNTL1 33323_r_at −49.5 SFN 202746_at −102.0 ITM2A 209386_at −49.6 TM4SF1 207154_at −104.8 DIO3 209591_s_at −49.9 BMP7 204273_at −113.3 EDNRB 212950_at −50.9 GPR116 230061_at −114.8 TM4SF18 211597_s_at −51.7 HOPX 235849_at −121.5 SCARA5 Higgins et al. www.pnas.org/cgi/content/short/1309970110 6of11 Table S2. Cont. Affymetrix ID FC (p0 vs. Intact DP) Gene symbol Affymetrix ID FC (p0 vs. Intact DP) Gene symbol 228434_at −52.2 BTNL9 205694_at −122.6 TYRP1 200986_at −53.6 SERPING1 229437_at −122.7 MIRN155 229623_at −53.8 FLJ12993 209436_at −131.0 SPON1 213332_at −54.2 PAPPA2 209686_at −157.7 S100B 236456_at −56.3 PTPN5 213994_s_at −164.0 SPON1 1556037_s_at −57.9 HHIP 222043_at −165.3 CLU 219867_at −59.4 CHODL 222885_at −174.2 EMCN 208982_at −60.7 PECAM1 227180_at −174.7 ELOVL7 208791_at −61.3 CLU 213975_s_at −187.2 LYZ 207670_at −62.4 KRT85 213456_at −195.8 SOSTDC1 209071_s_at −63.5 RGS5 202291_s_at −230.8 MGP 205229_s_at −64.2 COCH 213993_at −269.9 SPON1 203548_s_at −64.6 LPL 208399_s_at −316.1 EDN3 205328_at −65.7 CLDN10 218002_s_at −320.0 CXCL14 202878_s_at −68.9 CD93 200795_at −335.0 SPARCL1 202035_s_at −72.6 SFRP1 229839_at −339.3 SCARA5 213780_at −74.8 TCHH 222484_s_at −360.6 CXCL14 201348_at −76.3 GPX3 204712_at −372.4 WIF1 Fold changes (FC) are indicated. Negative values indicate a decrease in expression in p0. Table S3. Follicles induced after tissue recombination containing dermal spheroids from seven different donors No. of spheroids No. of follicles Donor no. placed in graft observed % inductivity D3 10 1 10 D4 8 5 62.5 D4 16 3 18.8 D4 15 6 40 D4 9 3 33.3 D8 20 0 0 D9 12 2 16.6 D10 12 1 8.3 D11 10 1 10 D11 10 3 30 D12 13 0 0 Higgins et al. www.pnas.org/cgi/content/short/1309970110 7of11 Table S4. 100/724 transcripts identified in territory T1 Gene symbol FC (F→p3) FC (F→S) Gene symbol FC (F→p3) FC (F→S) GREM1 320.4 101.3 FNDC1 19.4 2.6 MFAP5 171.1 32.2 COL11A1 19.3 −1.3 POSTN 152.3 35.0 MTHFD2 19.0 2.9 VGLL3 138.7 13.3 STC2 18.0 −1.5 SEMA3C 138.1 7.3 MKX 17.8 2.4 BCAT1 111.1 19.0 CITED2 17.6 2.6 RRAS2 67.9 18.8 ARSJ 17.5 3.3 ITGA11 61.8 7.5 GBP1 17.0 2.9 NEXN 61.3 2.8 RRM2 16.9 1.3 THBS1 61.1 17.6 CAP2 16.9 2.8 LOX 60.9 4.7 MYBL1 16.8 −1.3 WNT5B 52.4 12.4 B3GALT2 16.5 1.2 ACTC1 50.2 2.4 SLC7A5 15.9 2.5 PTPLA 49.9 14.9 FER1L3 15.8 4.7 CLGN 48.2 9.3 ASNS 15.6 1.0 GABBR2 48.1 2.9 ADAMTSL1 15.3 1.0 SLC38A1 44.4
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