[Staging of liver fibrosis in biliary atresia : Comparison of Chevallier and Ishak score as well as automated evaluation]. / Staging der Leberfibrose bei Gallengangatresie : Vergleich von Chevallier- und Ishak-Score sowie automatisierter Auswertung.

BACKGROUND: Biliary atresia (BA) is a rare disease of the newborn, resulting in liver cirrhosis due to obliterative cholangiopathy. Liver biopsies are commonly performed in order to confirm the diagnosis and in order to stage fibrosis. OBJECTIVES: The present study intended to analyze two established scores for evaluating liver fibrosis focusing on the interobserver variability as well as the prognostic reliability towards the time of liver transplantation. MATERIALS AND METHODS: Liver biopsies of BA patients between 2012 and 2015 were evaluated retrospectively by two pathologists at the Hannover Medical School (MHH) and the RWTH Aachen University Hospital. Fibrosis was measured using Ishak and Chevallier scores. Furthermore, a computerized automatically algorithm-based analyzation (ABAA) was performed. Results were evaluated towards the time point of liver transplantation and hepatoportoenterostomy (HPE). RESULTS: Overall, 34 liver biopsies were analyzed. The Ishak score showed a remarkable interobserver variability (ΚW = 0.68) while the Chevallier score was proven to have a poor interobserver variability (Fleiss' Κappa = -0.01). However, both scores were correlated positively, as was the ABAA (p < 0.001). Regarding prognostic reliability, ROC analyses of the Ishak score revealed the best validity towards an early liver transplantation within 12 months (AUC 0.813, p = 0.011). In addition, an increased Ishak score ≥4 reduced the survival time with the native liver (hazard ratio 6.6 [95% CI 1.9-23.3]). CONCLUSIONS: The Ishak score was revealed to have the best interobserver variability as well as prognostic validity towards an early liver transplantation in BA patients. Due to its easy applicability, the Ishak score was proven superior in comparison to the Chevallier score and ABAA. Therefore, use of the Ishak score is recommended in daily clinical routine for analyzing liver biopsies in BA patients.

[Adult autopsies during the past decade in Germany : Data from two university hospitals]. / Erwachsenenobduktionen im letzten Jahrzehnt in Deutschland : Daten zweier Universitätskliniken.

BACKGROUND: The clinical autopsy is the ultimate medical service for a patient and plays a crucial role in the education of physicians and other medical personnel, as well as in the context of quality control. Nevertheless, the number of autopsies is constantly decreasing. Numerous factors, such as the personal attitude of relatives and also clarification of relatives, as well as the increasing application of imaging methods while the patient is still alive, play a central role in this decline. OBJECTIVE: This study aimed to demonstrate the development of autopsy services over the past decade in two university hospitals in Germany and therefore to underline the importance of this investigation procedure in pathology. MATERIAL AND METHODS: Autopsy reports between the years 2005 and 2014 from 2 university institutes of pathology were analyzed regarding a diverse dataset, including age and sex of the deceased as well as the clinical and pathological causes of death. RESULTS: The data showed that the number of autopsies has continuously decreased over the past decade; however, the distribution of characteristics of the deceased remained relatively stable. In this cohort the clinically assumed cause of death differed from the pathological cause of death in 6% of the autopsies. Frequently occurring discrepant diagnoses were cardiac tamponade, aortic dissection and endocarditis/myocarditis. DISCUSSION: Our results show that, despite significant improvements in imaging methods, findings do not yield more accurate results than does autopsy. This underscores once again the need to encourage the performance of this final medical act on patients.

Hypoxia induces the expression of transketolase-like 1 in human colorectal cancer.

BACKGROUND AND AIMS: Transketolase-like (TKTL) 1 is one of the key enzymes for anaerobic sugar degradation even in the presence of oxygen (aerobic glycolysis). Transketolase-dependent reactions supply malignant tumors with ribose and NADPH. Therefore, TKTL1 activity could be crucial for tumor proliferation and survival. The aim of the study was to evaluate the expression of TKTL1 in colorectal cancer (CRC) and its regulation under hypoxic conditions. METHODS: We studied TKTL1 mRNA and protein expression in CRC cell lines and human CRC biopsies by quantitative real-time PCR, Western blotting and immunohistochemistry. Regulation of TKTL1 under oxygen depletion was analyzed by cultivating cells either in a three-dimensional spheroid model or in a hypoxia incubator chamber. RESULTS: TKTL1 mRNA was heterogeneously expressed in monolayers of cells with high levels in HT-29 and SW480. TKTL1 protein was also clearly detectable in HT-29 and SW480. Hypoxia-inducible factor (HIF)-1α protein expression correlated with TKTL1 protein expression in SW480 spheroids over time. On the one hand, induction of hypoxia in T84 spheroids did not induce TKTL1; on the other hand, hypoxia by incubation at 1% O2 in a hypoxia incubator chamber clearly showed an upregulation of TKTL1. In 50% of CRC patients, TKTL1 protein expression was upregulated in tumor compared to non-tumor tissue. The immunohistochemical staining of TKTL1 in CRC patient samples resulted in 14 positive and 30 negative samples. CONCLUSIONS: TKTL1 expression correlated with HIF-1α protein expression and was induced upon hypoxic conditions which could facilitate energy supply to tumors under these circumstances.

[Tumors of Vater's ampulla]. / Tumoren der Papilla Vateri.

Tumors of Vater's ampulla are generally uncommon. In this location intestinal type adenomas are frequently found, followed by noninvasive papillary neoplasms of the pancreaticobiliary type and neuroendocrine tumors (carcinoids). Carcinomas of Vater's ampulla represent about 0.5% of all gastrointestinal malignancies. Intestinal type adenocarcinoma is the most common malignant epithelial tumor followed by the pancreaticobiliary type adenocarcinoma. Highly malignant neuroendocrine carcinomas of Vater's ampulla are very uncommon. Carcinomas of the ampullary region can be sporadic or a component of several disease syndromes. Designation of large carcinomas as tumors with an ampullary or extra-ampullary origin can be difficult but is of relevance for a TNM conform classification. Helpful in the decision are the relationship between the tumor centre and Vater's ampulla, the existence of premalignant lesions in the ampullary epithelium as well as histology and immunostaining of the tumor.

[Mesenchymal stem cells and their interaction with biomaterials: potential applications in tissue engineering]. / Mesenchymale Stammzellen und ihre Interaktionen mit Biomaterialien: Anwendungsmöglichkeiten im Tissue-Engineering.

INTRODUCTION: Mesenchymal stem cells (MSC) are an important cell type for regenerative medicine and tissue engineering. They are involved in tissue regeneration by means of: (a) differentiation into specialised mesodermal cells and (b) their biosynthetic activity that is both immunomodulatory and trophic. In recent studies we analysed MSC in contact with different biomaterials to identify suitable combinations for tissue engineering. METHODS: A biomaterial test platform was established to analyse cell adhesion, viability, proliferation, cytotoxicity according to ISO 10993-5, apoptosis and differentiation to adipocytes and osteoblasts on a variety of polymers (degradable biopolymers, degradable synthetic polymers, non-degradable synthetic polymers, shape memory polymers, and ceramics). RESULTS: Using this platform, biomaterials which support MSC growth by maintaining their stem cell characteristics and support the differentiation of MSC towards mature osteoblasts were identified. Furthermore, we showed that MSC possess fibrinolytic capacities and perform extracellular matrix remodelling. CONCLUSION: The data support the theory that MSC are involved in tissue regeneration both via their differentiation capacity and their trophic characteristics. We identified different MSC/biomaterial combinations which are suitable for stem cell-based bone tissue engineering.

Endogenous myoglobin in human breast cancer is a hallmark of luminal cancer phenotype.

BACKGROUND: We aimed to clarify the incidence and the clinicopathological value of non-muscle myoglobin (Mb) in a large cohort of non-invasive and invasive breast cancer cases. METHODS: Matched pairs of breast tissues from 10 patients plus 17 breast cell lines were screened by quantitative PCR for Mb mRNA. In addition, 917 invasive and 155 non-invasive breast cancer cases were analysed by immunohistochemistry for Mb expression and correlated to clinicopathological parameters and basal molecular characteristics including oestrogen receptor-alpha (ERalpha)/progesteron receptor (PR)/HER2, fatty acid synthase (FASN), hypoxia-inducible factor-1alpha (HIF-1alpha), HIF-2alpha, glucose transporter 1 (GLUT1) and carbonic anhydrase IX (CAIX). The spatial relationship of Mb and ERalpha or FASN was followed up by double immunofluorescence. Finally, the effects of estradiol treatment and FASN inhibition on Mb expression in breast cancer cells were analysed. RESULTS: Myoglobin mRNA was found in a subset of breast cancer cell lines; in microdissected tumours Mb transcript was markedly upregulated. In all, 71% of tumours displayed Mb protein expression in significant correlation with a positive hormone receptor status and better prognosis. In silico data mining confirmed higher Mb levels in luminal-type breast cancer. Myoglobin was also correlated to FASN, HIF-2alpha and CAIX, but not to HIF-1alpha or GLUT1, suggesting hypoxia to participate in its regulation. Double immunofluorescence showed a cellular co-expression of ERalpha or FASN and Mb. In addition, Mb levels were modulated on estradiol treatment and FASN inhibition in a cell model. CONCLUSION: We conclude that in breast cancer, Mb is co-expressed with ERalpha and co-regulated by oestrogen signalling and can be considered a hallmark of luminal breast cancer phenotype. This and its possible new role in fatty acid metabolism may have fundamental implications for our understanding of Mb in solid tumours.

[Mesenchymal stem cells for bone tissue engineering]. / Mesenchymale Stammzellen für das "tissue engineering" des Knochens.

Human mesenchymal stem cells (MSC) represent an attractive option for cell replacement strategies (tissue engineering, TE). TE applications require stability of a stem cell/biomaterial-hybrid via cell migration, matrix-remodelling and differentiation. We focus on these mechanisms in organotypic culture systems for bone TE using MSC from the umbilical cord (UC-MSC) and from bone marrow (BM-MSC). For the organotypic differentiation of MSC into functional osteoblasts, MSC were embedded in a collagenous matrix and subjected to osteogenic differentiation. Under these culture conditions, UC-MSC exceeded BM-MSC in the expression and synthesis of extracellular matrix (ECM) proteins, while BM-MSC show enhanced osteogenic gene upregulation. In both cell types the biosynthetic activity was accompanied by the ultrastructural appearance of hydroxyapatite/calcium crystals. Following secretion of matrix metalloproteinases, both MSC types migrated into and colonised the collagenous matrix causing matrix strengthening and contraction. In conclusion, MSC promise a broad therapeutical application for a variety of connective tissues requiring ECM synthesis and remodelling.

[Characterisation of DNA methylation biomarkers for bladder cancer]. / Charakterisierung von DNA-Methylierungs-Biomarkern für das Harnblasenkarzinom.

Despite considerable advances in recent years in our understanding of the genetic changes occurring in urinary bladder cancer, similar progress in the field of epigenetics has hitherto been lacking. Increasingly, however, focus has shifted in the direction of aberrant DNA methylation as a result of recent studies showing the direct impact of such promoter hypermethylation on the loss of tumor suppressor gene expression and function, therefore potentially affecting tumor genesis and progression. The purpose of this study is the identification and characterization of new DNA methylation markers in urinary bladder cancer, with the expectation that these markers could then be incorporated in a multi-gene panel for clinical use in early cancer detection. In addition, better understanding of the signalling pathways involved will undoubtedly impact the development of new treatment strategies. Potential candidate genes, including the Wnt antagonist SFRP5 among others, will be validated by different epigenetic techniques using invasive and superficial urothelial cell lines as well as tumor and urine samples from bladder cancer patients.

[Status of the availability and use of next generation sequencing (NGS) in bladder cancer-a questionnaire within the uropathology working group]. / Status der Verfügbarkeit und Anwendung von "next generation sequencing" (NGS) beim Harnblasenkarzinom ­ eine Umfrage in der Arbeitsgemeinschaft Uropathologie.

BACKGROUND: Technical advancement and availability of high-throughput analysis has advanced molecular subtyping of most cancers. Thus, new possibilities for precision oncology have emerged. AIM: Therefore, we aimed to collect data regarding availability and use of next generation sequencing (NGS) for urothelial cancer within the uropathology working group of the German Society of Pathology. METHODS: We collected data by questionnaires and additionally asked for sequencing results of bladder cancers in the participating institutions. RESULTS: A total of 13 university-affiliated institutes of pathology took part in the survey. All university institutes offer NGS-based molecular panel diagnostics and provide panels covering between 15 and 170 genes. Altogether, only 20 bladder cancers were sequenced in routine diagnostics and for 10 cancers potential targeted treatment options were available. DISCUSSION: So far, despite availability of NGS diagnostics at university institutes of pathology, only few bladder cancer samples have been sequenced. Based on current data from the molecular subtyping of bladder cancers, we recommend a step-by-step protocol with basic immunohistochemistry analysis and subsequent subtype-dependent analyses, e.g., alterations of the fibroblast growth factor receptors (FGFR) or comprehensive gene panel analyses.

[Virilizing adrenal ganglioneuroma : A rare differential diagnosis in testosterone secreting adrenal tumours]. / Virilisierendes Ganglioneurom der Nebenniere : Eine seltene Differenzialdiagnose testosteronproduzierender Nebennierentumoren.

Testosterone secreting tumours of the adrenal glands are usually adrenal carcinomas or adenomas. Here we report the rare case of an adrenal ganglioneuroma with ectopic Leydig cells, a so-called virilizing adrenal ganglioneuroma. Clinically it is characterized by symptoms of virilization, histologically by the occurrence of a population of eosinophilic cells. In the absence of crystalloids of Reinke this cell population can be identified as Leydig cells based on positive immunohistochemical staining of inhibin and calretinin.

Frequent loss of SFRP1 expression in multiple human solid tumours: association with aberrant promoter methylation in renal cell carcinoma.

Oncogenic wingless-related mouse mammary tumour virus (Wnt) signalling, caused by epigenetic inactivation of specific pathway regulators like the putative tumour suppressor secreted frizzled-related protein 1 (SFRP1), may be causally involved in the carcinogenesis of many human solid tumours including breast, colon and kidney cancer. To evaluate the incidence of SFRP1 deficiency in human tumours, we performed a large-scale SFRP1 expression analysis using immunohistochemistry on a comprehensive tissue microarray (TMA) comprising 3448 tumours from 36 organs. This TMA contained 132 different tumour subtypes as well as 26 different normal tissues. Although tumour precursor stages of, for example kidney, colon, endometrium or adrenal gland still exhibited moderate to abundant SFRP1 expression, this expression was frequently lost in the corresponding genuine tumours. We defined nine novel tumour entities with apparent loss of SFRP1 expression, i.e., cancers of the kidney, stomach, small intestine, pancreas, parathyroid, adrenal gland, gall bladder, endometrium and testis. Renal cell carcinoma (RCC) exhibited the highest frequency of SFRP1 loss (89% on mRNA level; 75% on protein level) and was selected for further analysis to investigate the cause of SFRP1 loss in human tumours. We performed expression, mutation and methylation analysis in RCC and their matching normal kidney tissues. SFRP1 promoter methylation was frequently found in RCC (68%, n=38) and was correlated with loss of SFRP1 mRNA expression (p<0.05). Although loss of heterozygosity was found in 16% of RCC, structural mutations in the coding or promoter region of the SFRP1 gene were not observed. Our results indicate that loss of SFRP1 expression is a very common event in human cancer, arguing for a fundamental role of aberrant Wnt signalling in the development of solid tumours. In RCC, promoter hypermethylation seems to be the predominant mechanism of SFRP1 gene silencing and may contribute to initiation and progression of this disease.

Long-term survival and bipotent terminal differentiation of human mesenchymal stem cells (hMSC) in combination with a commercially available three-dimensional collagen scaffold.

Researchers working in the field of tissue engineering ideally combine autologous cells and biocompatible scaffolds to replace defect tissues/organs. Due to their differentiation capacity, mesenchym-derived stem cells, such as human mesenchymal stem cells (hMSC), are a promising autologous cell source for the treatment of human diseases. As natural precursors for mesenchymal tissues, hMSC are particularly suitable for bone, cartilage, and adipose tissue replacement. In this study a detailed histological and ultrastructural analysis of long-term cultured and terminally differentiated hMSC on 3D collagen scaffolds was performed. Standardized 2D differentiation protocols for hMSC into adipocytes and osteoblasts were adapted for long-term 3D in vitro cultures in porous collagen matrices. After a 50-day culture period, large numbers of mature adipocytes and osteoblasts were clearly identifiable within the scaffolds. The adipocytes exhibited membrane free lipid vacuoles. The osteoblasts were arranged in close association with hydroxyapatite crystals, which were deposited on the surrounding fibers. The collagen matrix was remodeled and adopted a contracted and curved form. Human MSC survive long-term culture within these scaffolds and could be terminally differentiated into adipocytes and osteoblasts. Thus, the combination of hMSC and this particular collagen scaffold is a possible candidate for bone and adipose tissue replacement strategies.

[Update on urothelial carcinoma histopathology]. / Aktuelles zur Histopathologie des Harnblasenkarzinoms.

Urothelial carcinoma comprise a heterogenous group of diseases with very different clinical outcome: 70%-80% of urothelial carcinoma are genetically stable and associated with a favorable prognosis, while 20%-30% are genetically unstable and have a high progression rate. Therefore, the current WHO Classification (2004) reduces the histologic grade to simply 'low grade' and 'high grade'. In addition to TNM classification and histologic grade, genetic factors such as p53 mutations, fibroblast growth factor receptor 3 (FGFR3) and phosphatidylinositol-3-kinase (PIC(3)CA) are relevant in a patient's prognosis.

[Nested-variant urothelial carcinoma. Case report and molecular aspects]. / Die Nested-Variante des Urothelkarzinoms. Fallbericht und molekulare Aspekte.

The nested variant of urothelial carcinoma is a rare urothelial neoplasia which is characterized by relatively bland morphology and early muscle-invasive growth. We report on a 65-year-old male patient with a non-invasive high-grade urothelial lesion (carcinoma in situ and pTa G3). After treatment with BCG an invasive urothelial carcinoma was discovered whereas the carcinoma in situ had disappeared. Examination of the bladder specimen showed a nested-variant urothelial carcinoma. Molecular analyses indicated a de-novo genesis of the invasive urothelial carcinoma.

[Precancerous lesions of the urothelium. From Feulgen staining to single cell CGH]. / Präkanzerosen des Urothels. Von der Feulgen-Färbung bis zur Einzelzell-CGH.

Feulgen staining represents a staining method to quantitatively document the DNA content of a nucleus. Thus it is an excellent and straightforward method to reflect the irregular increase in DNA content of a malignant cell as a sign of genetic instability. Genetic instability of the tumour cell is the key feature of the 2004 WHO classification of bladder tumours, in which flat and papillary neoplasia are grouped into low- and high-grade lesions. "High grade" represents the tumor with genetic instability and consequently a higher likelihood of progression. Concomitant distinct genetic aberrations other than the numeric ones are increasingly identified as discriminators and help group the entities. The current status of genetic investigations, especially those in precancerous lesions, will be outlined in this review in the context of morphology (histology and cytology) as well as clinical situation.

[Promoter methylation of ID4. A marker for recurrence-free survival in human breast cancer]. / Promotormethylierung von ID4. Ein Marker für die Rezidivbildung des humanen Mammakarzinoms.

The aim of this study was to unravel the role of the transcription factor inhibitor of DNA binding 4 (ID4) in human breast carcinogenesis in more detail, especially the impact of ID4 promoter methylation on disease progression. Demethylating treatment of breast cancer cell lines was associated with ID4 reexpression. ID4 promoter methylation was frequently observed in primary breast cancer samples (68.9%, 117/170). We found a very tight correlation (p<0.001) between ID4 promoter methylation and loss of ID4 mRNA expression in these specimens. For breast tissue as the first tumour entity analyzed in detail, we could show a direct correlation between ID4 promoter methylation and loss of ID4 expression on both the mRNA and protein level. Interestingly, ID4 promoter methylation was a factor for unfavourable recurrence-free survival (p=0.036) and increased the patient's risk for lymph node metastases (p=0.030). Our data suggest that ID4 is a potential tumour suppressor gene in human breast tissues that undergoes epigenetic silencing during carcinogenesis, leading to an increased risk for tumour relapse. Thus, ID4 methylation status could serve as a prognostic biomarker in human breast cancer.

[Urothelial carcinoma in situ of the seminal vesicles--an indicator of tumour multifocality]. / Urotheliales Carcinoma in situ der Samenblasen--Ausdruck von Tumormultifokalität.

We report a case of multifocal urothelial carcinoma in situ of the left ureter with early stromal invasion and concomitant in situ lesions in bladder, prostate and seminal vesicle. After complete topographical mapping of the cystoprostatovesiculectomy specimen the unusual manifestation of urothelial carcinoma in situ in a seminal vesicle turned out to be a tumour spread via the ductus ejaculatorius into the seminal vesicle. DNA sequencing of the tumour suppressor gene TP53 of different tumour lesions revealed identical wild-type sequences.

[Novel prognostic marker in invasive breast cancer. ITIH5 expression is abrogated by aberrant promoter methylation]. / Neuer Prognosemarker beim invasiven Mammakarzinom. ITIH5-Expression wird über aberrante Promotormethylierung inaktiviert.

We have recently characterized ITIH5 as a new extracellular matrix protein that exhibits clear expression loss in a variety of human tumour entities, including breast cancer. The aim of the present study was to decipher the molecular cause of ITIH5 expression loss in breast cancer and to learn more about the possible role of this molecule in cancer diseases. ITIH5 protein expression was found to be strongly reduced in 42% of invasive breast carcinomas-interestingly, with significant association with poor patient outcome. ITIH5 promoter methylation was frequently detected in breast cell lines and in primary carcinomas (40%), and it was functionally correlated with loss of ITIH5 mRNA expression. Moreover, ITIH5 promoter methylation was also significantly associated with poor clinical patient outcome and also with the occurrence of lymph node and distant metastases. In conclusion, we propose that ITIH5 may represent a novel metastasis repressor in human breast cancer. Both ITIH5 protein expression and ITIH5 promoter methylation may serve as prognostic biomarkers, thereby helping improve clinical patient outcome.

Aberrant methylation of the Wnt antagonist SFRP1 in breast cancer is associated with unfavourable prognosis.

The canonical Wnt signalling pathway plays a key role during embryogenesis and defects in this pathway have been implicated in the pathogenesis of various types of tumours, including breast cancer. The gene for secreted frizzled-related protein 1 (SFRP1) encodes a soluble Wnt antagonist and is located in a chromosomal region (8p22-p12) that is often deleted in breast cancer. In colon, lung, bladder and ovarian cancer SFRP1 expression is frequently inactivated by promoter methylation. We have previously shown that loss of SFRP1 protein expression is a common event in breast tumours that is associated with poor overall survival in patients with early breast cancer. To investigate the cause of SFRP1 loss in breast cancer, we performed mutation, methylation and expression analysis in human primary breast tumours and breast cell lines. No SFRP1 gene mutations were detected. However, promoter methylation of SFRP1 was frequently observed in both primary breast cancer (61%, n=130) and cell lines analysed by methylation-specific polymerase chain reaction (MSP). We found a tight correlation (P<0.001) between methylation and loss of SFRP1 expression in primary breast cancer tissue. SFRP1 expression was restored after treatment of tumour cell lines with the demethylating agent 5-aza-2'-deoxycytidine. Most interestingly, SFRP1 promoter methylation was an independent factor for adverse patient survival in Kaplan-Meier analysis. Our results indicate that promoter hypermethylation is the predominant mechanism of SFRP1 gene silencing in human breast cancer and that SFRP1 gene inactivation in breast cancer is associated with unfavourable prognosis.

Mesenchymal stem cells can be recruited to wounded tissue via hepatocyte growth factor-loaded biomaterials.

Mesenchymal stem cells (MSC) are precursor cells of mesodermal tissue and, because of their trophic phenotype, they are known to play beneficial roles in wound healing. In addition, various tissue engineering strategies are based on MSC/biomaterial constructs. As the isolation and expansion of MSCs is a long-term process, a major goal is to develop an endogenous stem cell recruitment system that circumvents all ex vivo steps generally used for tissue engineering. Therefore collagen and silk fibroin were loaded with hepatocyte growth factor (HGF), a chemoattractant for MSCs. Collagen was mixed with HGF during polymerization, while silk fibroin and HGF were produced as fusion proteins by transgenic silkworms. To demonstrate release of active HGF, enzyme-linked immunosorbent assay, in vitro migration assays and animal studies were performed to demonstrate MSC migration in vivo, followed by detailed examinations of the immunological effects of the biomaterials. Hepatocyte growth factor was released burst-like, both from silk fibroin and collagen during the first 8 h and gradually for up to 168 h in vitro. Directed migration in vitro was demonstrated when MSCs were exposed to HGF. In vivo, HGF-loaded collagen and silk fibroin were tolerated as subcutaneous implants. In addition, it was proved that endogenous MSCs were recruited from the local environment. These results show for the first time recruitment of endogenous MSCs to HGF-loaded collagen (fast degradable) and silk fibroin scaffolds (long-term degradable) in vitro and in vivo. This knowledge could be applied to make off-the-shelf, readily available constructs for use in patients with chronic wound or burns. Copyright © 2016 John Wiley & Sons, Ltd.