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Histopathological analysis of human specimens removed from the injection area of expanded adipose-derived stem cells: Correspondence

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Histopathological analysis of human specimens removed from the injection area of expanded adipose-derived stem cells: Correspondence
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  (21 of 26) of SHH-positive chordomas and in oneBNCT. SHH and PTCH1 were both detected in humanfetal notochord at 12 and 28 weeks gestational age,but not at 24 or 34 weeks. All five intervertebral discswere negative for PTCH1. SHH and PTCH1 werecoexpressed in 62% (eight of 13) of chondrosarcomas.SHH and its cognate receptor PTCH1 are coexpressedin human notochord, at least up to 28 weeks gesta-tional age. Whereas SHH and PTCH1 are observed lessfrequently in notochord obtained later in developmentand in the mature nucleus pulposus, this receptor– ligand pair is coexpressed in most chordomas, raisingthe possibility that autocrine or paracrine SHH signal-ling may be important for the neoplastic transforma-tion of notochordal rests or BNCTs. The status of theSHH signalling pathway in BNCT is unclear, andfurther study of additional cases is required. In addi-tion, given the important role of the Indian hedgehogsignalling in chondrogenesis, 6 this pathway may alsobe activated aberrantly in malignant cartilage tu-mours. Whether aberrant activation of this signallingpathway contributes to chordomagenesis should beinvestigated further in putative precursor lesions andmurine models of chordoma in development. 4  Justin M M Cates 1 Doha M Itani 1 Cheryl M Coffin 1 Brian D Harfe 2 1 Department of Pathology,Vanderbilt University Medical Center, Nashville, TN, and  2 Department of Molecular Genetics and Microbiology,University of Florida, Gainesville, FL, USA 1. Vujovic S, Henderson S, Presneau N  et al.  Brachyury, a crucialregulator of notochordal development, is a novel biomarker forchordomas.  J. Pathol.  2006;  209;  157–165.2. Yamaguchi T, Watanabe-Ishiiwa H, Suzuki S, Igarashi Y, Ueda Y.Incipient chordoma: a report of two cases of early-stage chordomaarising from benign notochordal cell tumors.  Mod. Pathol.  2005; 18;  1005–1010.3. Chari NS, McDonnell TJ. The sonic hedgehog signaling network indevelopment and neoplasia.  Adv. Anat. Pathol.  2007;  14;  344– 352.4. Choi KS, Cohn MJ, Harfe BD. Identification of nucleus pulposusprecursor cells and notochordal remnants in the mouse: implica-tions for disk degeneration and chordoma formation.  Dev. Dyn. 2008;  237;  3953–3958.5. Kelley MJ, Korczak JF, Sheridan E, Yang X, Goldstein AM, ParryDM. Familial chordoma, a tumor of notochordal remnants, islinked to chromosome 7q33.  Am. J. Hum. Genet.  2001;  69;  454– 460.6. Goldring MB, Tsuchimochi K, Ijiri K. The control of chondrogen-esis.  J. Cell. Biochem.  2006;  97;  33–44. Histopathological analysis of humanspecimens removed from the injection areaof expanded adipose-derived stem cells DOI: 10.1111/j.1365-2559.2010.03573.x Sir  : Perianal fistulas are the most common type of gastrointestinal fistula and their negative effect onquality of life has long been recognized. 1 After prom-ising results in a Phase I trial of treatment of perianalcomplex fistula with adipose-derived adult stem cells(ASCs), 2 a Phase II clinical trial evaluated the safetyand efficacy of this novel therapy. The proportion of patients with fistula healing was significantly higherfor ASCs (71%), recurrences in the first year were rareand no treatment-associated adverse effects werereported. 3 However, we know very little about the fateof these cells after implantation, the only previousreport being a cardiac biopsy suggesting long-term cellviability. 4 Here, we describe the histological andelectron microscopic findings from five unscheduled Table 1.  Prevalence of SHHand PTCH1 expressionin chordoma, benignnotochordal cell tumour,chordoid tissues andchondrosarcomaSHH PTCH1Chordoma 22  ⁄    23 (96%) 18  ⁄    22 (82%)Chondroid chordoma 5  ⁄    5 (100%) 4  ⁄    5 (80%)BNCT 2  ⁄    4 (50%) 1  ⁄    4 (25%)Notochord 3  ⁄    6 (50%) 2  ⁄    6 (33%)IVD 3  ⁄    8 (38%) 0  ⁄    5 (0%)Chondrosarcoma 13  ⁄    16 (81%) 8  ⁄    16 (50%)IVD, intervertebral disc; BNCT, benign notochordal cell tumour; PTCH1, patched homologue1; SHH, sonic hedgehog homologue. Correspondence  979   2010 Blackwell Publishing Ltd,  Histopathology ,  56,  968–982.  biopsies taken up to 2 years after ASC implantation toprovide further support for the safety of ASC therapy.The biopsy specimens were obtained from the externalfistula opening of two female and three male partici-pants in the Phase II study (age 35–45 years) at1 month (two biopsies), 12 months, 19 months and24 months post-implantation for different clinical rea-sons.For histology, surgical samples were fixed in 10%buffered formalin and embedded in paraffin. Four-micrometre-thick sections were stained with haemat-oxylin and eosin. For electron microscopy, surgicalsamples (1 month and control) were fixed, postfixed,rinsed, dehydrated and embedded in Araldite (Durcu-pan, Fluka, Buchs, Switzerland). Serial 1- l m semithinsections and ultrathin sections (70 nm) were used tostudy cell organization.The intensity and type of inflammatory infiltrate,grade of fibrosis and presence or absence of granulom-atous tissue or neoplastic cells were recorded. Histo-logical studies of the two biopsy specimens taken1 month after cell implantation revealed a chronicinflammatory infiltrate and weak scar tissue withgranuloma formation (Figure 1A). The biopsy speci-mens at 19 months and 2 years showed acute infiltra-tion around the fistulous tract, minimal perivascularchronic inflammatory infiltrate in the scar tissue andsevere epidermal ulceration (Figures 1B,C and 2A–I)with no evidence of neoplastic tissue. Electron micros-copy showed normal tissue (Figure 2A–I) with highlyvascularized areas with abundant collagen fibres ina coronal and transverse alignment (Figure 2E,H)and fibroblasts (Figure 2E), with areas of stratifiedepithelium and normal ultrastructural features (Fig-ure 2E–I). Smooth muscle was also found in compactbundles with different alignments and projections(Figure 2I, arrows).Mesenchymal stem cells have been shown toimprove wound healing in experimental modelsthrough accelerated wound closure with increasedre-epithelialization, cellularity and angiogenesis 5 andpossibly through a paracrine effect. 6 Our results showfistula healing at the implanted area. By the firstmonth, processes indicative of healing were observed, Figure 2.  Histological and electron microscopy analysis of perianal fistula treated with ASCs. Macroscopically notable changes were notobserved in biopsies from ASC-treated fistualas ( B ) compared with untreated fistual ( A ). H&E staining showed normal features of perianal tissuewith stratified epithelium (black arrow) ( C  and  D ). Electron microscopy studies showed few fibroblasts embedded in a collagen matrix ( E ), somemelanocytes (white arrows) with normal features and a stratified epithelium with a fine basal lamina (black arrows) ( F ). Occasionally,myelinated axons (asterisk) were observed between connective tissue ( G ) indicating normal regeneration. In  H , electron microsopcy showedportions of collagen fibers sectioned transversely ( o ) or obliquely (x). ( I ) In addition, smooth muscle (arrows) was present in compact bundleswith different alignments and projections. Scale bar: 7 mm ( A , B ); 4 mm ( C ); 0.5 mm ( D ) 5  l g ( E ); 10  l m ( F ); 1  l m ( G ); 0.5  l m ( H ); 10  l m ( I ).f, Fribroblasts; c, collagen; B, basal layer; CT connective tissue. ABC Figure 1.  Histological studies. The biopsy taken at 1 month after cellimplantation shows fibrous scar tissue and a discrete perivascularchronic inflammatory infiltrate ( A ). Similar morphological changesare observed in the biopsies taken at 19 months ( B ) and 24 months( C ) after cell implant. 980  Correspondence   2010 Blackwell Publishing Ltd,  Histopathology ,  56,  968–982.  c cffcc BL L CT T   ccffccBLCTA BC DE F xo xoGHI Correspondence  981   2010 Blackwell Publishing Ltd,  Histopathology ,  56,  968–982.  with highly vascularized areas with abundant collagenfibres and fibroblasts on a matrix glycoprotein (neo-vascularization is a crucial step in the wound-healingprocess 1,7 ) and areas of stratified epithelium andnormal ultrastructural features without any signs of rejection of implanted ASCs.As implanted ASCs could not be labelled for safetyreasons, identification of biopsy cells derived from ASCswas impossible. However, study of the ASC-implantedarea showed improved fistula healing, although theASC-mediated mechanisms responsible for thisimprovement are not well defined.Another pertinent question is the safety of ASC usein human cell therapies. Despite certain controversy,our results showed no cellular changes over time thatmight indicate the presence of tumour cells or neo-plastic processes for up to 2 years.To our knowledge, this is the first time that severalbiopsy specimens–taken at different times–of regionsinjected with ASCs have been studied. Taken together,our data suggest that  ex vivo  expanded ASCs have abeneficial effect on the healing process and support thesafety of this type of human cell therapy in the perianalregion. Mariano Garcı´a-Arranz 1,2 Ulises Go´mez-Pinedo 3 David Hardisson 2,4 Dolores Herreros 5 He´ctor Guadalajara 5 Ignacio Garcı´a-Go´mez 2  Jose´ Manuel Garcı´a-Verdugo 3,6 Damia´n Garcı´a-Olmo 1,2,5 1 Cell Therapy Laboratory, Foundation by BioclinicalInvestigation of La Paz University Hospital-IdiPAZ,Paseo de la Castellana 261, 28046 Madrid, 2 School of Medicine, Autonomous University of Madrid-IdiPAZ, Madrid, 3 Cell Morfology Laboratory,CIFP and CIBERNED, Valencia, 4 Department of Pathology, La Paz UniversityHospital-IdiPAZ. Madrid, 5 Surgery Unit, La Paz UniversityHospital-IdiPAZ, Madrid, and  6 Cavanilles Institut, University of Valencia, Spain 1. Garcı´a-Aguilar J, Davey CS, Le CT, Lowry AC, Rothenberger DA.Patient satisfaction after surgical treatment for fistula-in-ano.  Dis.Colon Rectum  2000;  43;  1206–1212.2. Garcı´a-Olmo D, Garcı´a-Arranz M, Herreros D, Pascual I, Peiro C,Rodrı´guez-Montes JA. A phase I clinical trial of the treatment of Crohn’s fistula by adipose mesenchymal stem cell transplantation. Dis. Colon Rectum  2005;  48;  1416–1423.3. Garcia-Olmo D, Herreros D, Pascual I  et al.  Expanded adipose-derived stem cells for the treatment of complex perianal fistula: aphase II clinical trial.  Dis. Colon Rectum  2009;  52;  79–86.4. Hage`ge AA, Carrion C, Menasche´ P  et al.  Viability and differen-tiation of autologous skeletal myoblast grafts in ischaemiccardiomyopathy.  Lancet  2003;  361;  491–492.5. Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cellsenhance wound healing through differentiation and angiogenesis. Stem Cells  2007;  25;  2648–2659.6. Chen L, Tredget EE, Wu PY, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endotheliallineage cells and enhance wound healing.  PLoS ONE . 2008;  3; E1886–E1894.7. Arnold F, West DC. Angiogenesis in wound healing.  Pharmacol.Ther.  1991;  52;  407–422. 982  Correspondence   2010 Blackwell Publishing Ltd,  Histopathology ,  56,  968–982.

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