京都大学 / 新制・課程博士 / 博士(医学) / 甲第23370号 / 医博第4739号 / 新制||医||1051(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 椛島 健治, 教授 竹内 理, 教授 森信 暁雄 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

Breast cancer is a highly heterogeneous disease with multiple drivers and a complex regulatory network. Periostin (Postn) is a matricellular protein involved in a plethora of cancer types and other diseases. More specifically, Postn has been shown to be involved in various processes of tumor progression such as angiogenesis, cell survival, invasion, and metastasis. A high Postn level in breast cancer has been corelated with a more aggressive phenotype. Despite extensive research, it remains unclear what Postn is doing to the cancer environment and how cancer cells regulate Postn. Here, we assessed the role and regulation mechanisms of Postn in ErbB2-mediated tumorigenesis. By crossing Postn deficient animals into the oncogenic NeuNDL model of ErbB2-positive breast cancer, we have shown that Postn deletion delays tumor onset and increases overall survival by affecting proliferation and apoptosis. These tumors also showed a decrease in collagen deposition which is the proposed mechanism for its effect in vivo. Using isolated cancer cells from the Postn deficient background we assessed re-expression of Postn which had no effect on in vitro tumorigenesis processes or in vivo subcutaneous growth in immunodeficient mice. Furthermore, we established an in vitro model to study the regulation of Postn using a bovine pituitary gland derived extract as a natural repressor of Postn. Using mass spectrometry and RNA sequencing, we identified potential regulators of Postn gene expression. We also showed a cross regulation between FGFR, TGFβ and PI3K/AKT pathways to regulate Postn expression. In ErbB2-mediated murine breast cancer cells, we found that TGFβ can induce Postn expression in a SMAD-independent manner while bFGF can repress Postn expression through a PKC-dependent pathway. Postn induction and repression by TGFβ and bFGF respectively, are both dependent on PI3K/AKT signaling. Overall, these results suggest a cancer-driving function for Postn and reveal a novel mechanism for regulating Postn expression.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21639号 / 医博第4445号 / 新制||医||1034(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 濵﨑 洋子, 教授 小池 薫, 教授 清水 章 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Perisotin-like-factor (PLF) is a member of the Fasciclin family of proteins, which are characterized by the presence of 150 amino acid long conserved Fasciclin domains. Members of this family have been implicated in numerous cellular processes like adhesion, migration, axonal guidance and growth cone extension. PLF plays an important role during embryonic development, however very low levels are present in adults. PLF is up regulated in adult tissues when they are exposed to stress or insult. We have previously shown that PLF is up regulated in heart when they are mechanically overloaded and in lung when exposed to cigarette smoke. Similarly in bone, PLF is highly up regulated in fractured bone calli, albeit not present in normal adult bone. Furthermore PLF leads to increased bone formation in vivo in the bone marrow cavity when over expressed adenovirally. These results suggest that PLF promotes tissue repair and healing after injury. Additionally, PLF expression was up regulated in musculoskeletal tissues in our innovative model of Upper extremity-Work Related Musculoskeletal Disorder (WMSD). In this model, which draws parallels between the exposure to risk factors and development of associated disorders in human PLF was expressed in bone, skeletal muscle, tendon and nerves. Coincidentally, these are the same tissues in which PLF is expressed during embryonic development. Additionally, PLF was detected in inflammatory cells like macrophages suggesting a role for PLF in inflammation. Molecules like PLF which play important roles during development, reappear when the tissues require them, promoting their remodeling and recovery can be targeted as therapeutic agents. Such molecules can be targeted after injury or disease. In this study we focus our attention on the role of PLF in musculoskeletal (muscle and bone) remodeling in our animal model of WMSD. / Anatomy

Doença respiratória exacerbada por aspirina, conhecida como AERD (Aspirin exacerbated respiratory disease) é caracterizada por rinossinusite crônica eosinofílica, polipose nasossinusal, asma e hipersensibilidade a aspirina e outros anti-inflamatórios não-esteroidais. Expressão aumentada do biomarcador periostina foi descrita em pacientes com AERD, em tecido nasossinusal, incluindo membrana basal, matriz extracelular e pólipo nasal. Avaliamos níveis de periostina sérica em pacientes com AERD e comparamos com níveis em pacientes com rinite alérgica perene (RAP) e indivíduos saudáveis. Foram selecionados 29 pacientes (20F/9M) com diagnóstico de AERD, dentre aqueles atendidos nos Ambulatórios de Alergia e de Otorrinolaringologia do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (HCFMRP-USP). Estes pacientes realizaram exames confirmatórios, incluindo teste de provocação oral com aspirina, e foram submetidos a biópsia de pólipos nasais por nasofibroscopia. Como controles, foram selecionados 12 pacientes com RAP (9F/3M) e 23 indivíduos saudáveis (14F/9M). Eosinófilos foram quantificados em sangue periférico e em tecido de pólipo ou mucosa nasal. IgE total foi determinada por ImmunoCAP, e periostina sérica foi medida por ELISA. Número de eosinófilos teciduais por campo de grande aumento (CGA), número de eosinófilos por milímetro cúbico em sangue periférico, níveis de IgE total e de periostina sérica em pacientes com AERD foram comparados aos de pacientes com RAP e indivíduos saudáveis. Pacientes com AERD tinham idade maior (mediana 54 anos, faixa 22-60) que pacientes com RAP (mediana 30 anos, faixa 19-57, p=0,0001) e indivíduos saudáveis (mediana 29 anos, faixa 19-53, p=0,0001), sem diferença entre os sexos. Números de eosinófilos em sangue periférico e em tecido foram mais elevados em pacientes com AERD que em pacientes com RAP e indivíduos saudáveis. A mediana do número de eosinófilos em sangue periférico foi 640eos/µL (faixa 100-5.100); 200eos/µL (faixa 100-500); e 100 eos/µL (faixa 100-400) em pacientes com AERD, RAP e indivíduos saudáveis, respectivamente (AERD versus RAP, p=0,0003; AERD versus indivíduos saudáveis, p=0,01). A média do número de eosinófilos teciduais foi de 113,3células/CGA; 2,5células/CGA; e 0,7células/CGA, respectivamente (AERD versus RAP, p=0,017; AERD versus indivíduos saudáveis p=0,003). A média geométrica da IgE total foi de 290,18kU/L (faixa 59,5-8.140); 69,96kU/mL (faixa 5,5-898); e 43,14kU/mL (faixa 4- 1.328) em pacientes com AERD, RAP e indivíduos saudáveis, respectivamente, sem diferença entre os grupos. Periostina sérica foi mais elevada em pacientes com AERD quando comparados a indivíduos saudáveis. A mediana de periostina sérica foi de 602ng/ml (faixa 290,7-1.055); 535,6ng/mL (faixa 209-733,2); e 496,7mg/mL (faixa 327,4-713,4), em pacientes com AERD, RAP e indivíduos saudáveis, respectivamente (AERD versus indivíduos saudáveis, p=0,01). Em subgrupo de pacientes brasileiros com AERD, observamos elevado número de eosinófilos em sangue periférico e em tecido, quando comparados a pacientes com RAP e indivíduos saudáveis. Níveis mais elevados de periostina sérica foram observados em pacientes com AERD, quando comparados a indivíduos saudáveis, indicando forte resposta do tipo 2 em pacientes com AERD em nosso meio / Aspirin exacerbated respiratory disease (also known as AERD), is characterized by eosinophilic chronic hypertrophic rhinosinusitis, nasosinusal polyps, asthma and hypersensitivity to Aspirin or other non-steroidal anti-inflammatory drugs. A higher expression of the biomarker periostin has been described in patients with AERD, in nasosinusal tissue, including basal membrane, extracellular matrix and nasal polyps. We evaluated the levels of serum periostin in patients with AERD, and compare those levels with patients with perennial allergic rhinitis (PAR), and with healthy subjects. Twenty-nine patients (20F/9M) with AERD were selected from the Allergy and Otolaryngology Clinics, from the Clinical Hospital of the Ribeirão Preto Medicine School, University of São Paulo (HCFMRP-USP). Those patients underwent confirmatory exams, such as Oral Provocation test with aspirin, and were submitted to polyp biopsy through nasofibroscopy. As a control group, 12 patients (9F/3M) with PAR and 23 healthy subjects (14F/9M) were selected. Eosinophils were quantified in peripheral blood and in polyp tissue or nasal mucosa. Total IgE was determined by ImmunoCAP, and serum periostin was measured by ELISA. The number of tissue eosinophils by high magnification field (HMF), number of eosinophils by cubic milliliter in peripheral blood, total IgE levels and serum periostin levels in patients with AERD were compared with those from patients with PAR and healthy subjects. Patients with AERD were older (median 54 years, and range 22-60) than patients with PAR (median 30 years, range 19-57, p=0,0001) and healthy subjects (median 29 years, range 19-53, p=0,0001), with no difference between genders. The numbers of eosinophils in peripheral blood and in tissue were higher in patients with AERD than patients with PAR or healthy subjects. The median of eosinophil number in peripheral blood was 640eos/µL (range 100-5.100); 200eos/µL (range 100-500); e 100eos/µL (range 100-400) in patients with AERD, PAR and healthy subjects respectively (AERD vs PAR, p=0,0003; AERD vs healthy subjects, p=0,01). The average number of tissue eosinophils was 113,3cels/HMF; 2,5cels/HMF; e 0,7cels/HMF, respectively (AERD vs PAR, p=0,017; AERD vs healthy subjects, p=0,003). The geometric mean for total IgE was 290,18kU/mL (range 59,5-8.140); 69,96kU/mL (range 5,5-898); and 43,14kU/mL (range 4-1.328) in patients with AERD, PAR and healthy subjects respectively, with no difference between the groups. Serum periostin was higher in patients with AERD when compared with healthy subjects. The median for serum periostin was 602ng/ml (range 290,7-1.055); 535,6ng/mL (range 209-733,2); e 496,7ng/mL (range 327,4-713,4), in patients with AERD, PAR and healthy subjects respectively (AERD vs healthy subjects, p=0,01). In a Brazilian subgroup of patients with AERD, we observed an elevated number of eosinophils in peripheral blood and tissue, when compared with patients with PAR and healthy subjects. Higher levels of serum periostin were observed in patients with AERD, when compared with healthy subjects, indicating a strong type 2 response in patients with AERD in our environment.

Breast cancer is the most common cancer in female population worldwide. In addition to mutations, the breast tumor microenvironment especially the tumor cell - stroma interactions through extracellular matrix components and multiple growth factors have been shown to promote tumor progression. Among those, increases in both TGF-β (transforming growth factor beta) activities and periostin expression were associated with tumor cell survival, proliferation and metastasis. TGF-β role in breast cancer progression including its ability to promote periostin expression has been extensively studied. In contrast, the role of periostin in cancer progression remains to be fully understood. Thus, the present study aimed to determine whether TGF-β and periostin have effect on each other’s expressions in breast tumor and stroma cells using in vitro cell models. Through Western blot analyses and ELISAs, the periostin and TGF-β expressions of both stroma and tumor cells were analyzed following TGF-β and periostin treatments, respectively. The results indicate that TGF-β treatments led to significant increase in periostin expression in fibroblasts (p<0.05). In addition, periostin was differentially expressed by human breast cancer cells following TGF-β1 treatment. The TGF-β activities involved activation of pSMAD2 in both L929 fibroblasts and MCF10A mammary cells. Taken together, all experimental data indicate that within the breast tumor TGF-β and periostin likely participate in a regulation loop. Whether this putative regulation loop is critical to metastasis remains to be determined. Should periostin play a critical role in breast cancer progression, it could become a specific target in the preventive and/or therapeutic development of breast cancer patients.

Doença respiratória exacerbada por aspirina, conhecida como AERD (Aspirin exacerbated respiratory disease) é caracterizada por rinossinusite crônica eosinofílica, polipose nasossinusal, asma e hipersensibilidade a aspirina e outros anti-inflamatórios não-esteroidais. Expressão aumentada do biomarcador periostina foi descrita em pacientes com AERD, em tecido nasossinusal, incluindo membrana basal, matriz extracelular e pólipo nasal. Avaliamos níveis de periostina sérica em pacientes com AERD e comparamos com níveis em pacientes com rinite alérgica perene (RAP) e indivíduos saudáveis. Foram selecionados 29 pacientes (20F/9M) com diagnóstico de AERD, dentre aqueles atendidos nos Ambulatórios de Alergia e de Otorrinolaringologia do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (HCFMRP-USP). Estes pacientes realizaram exames confirmatórios, incluindo teste de provocação oral com aspirina, e foram submetidos a biópsia de pólipos nasais por nasofibroscopia. Como controles, foram selecionados 12 pacientes com RAP (9F/3M) e 23 indivíduos saudáveis (14F/9M). Eosinófilos foram quantificados em sangue periférico e em tecido de pólipo ou mucosa nasal. IgE total foi determinada por ImmunoCAP, e periostina sérica foi medida por ELISA. Número de eosinófilos teciduais por campo de grande aumento (CGA), número de eosinófilos por milímetro cúbico em sangue periférico, níveis de IgE total e de periostina sérica em pacientes com AERD foram comparados aos de pacientes com RAP e indivíduos saudáveis. Pacientes com AERD tinham idade maior (mediana 54 anos, faixa 22-60) que pacientes com RAP (mediana 30 anos, faixa 19-57, p=0,0001) e indivíduos saudáveis (mediana 29 anos, faixa 19-53, p=0,0001), sem diferença entre os sexos. Números de eosinófilos em sangue periférico e em tecido foram mais elevados em pacientes com AERD que em pacientes com RAP e indivíduos saudáveis. A mediana do número de eosinófilos em sangue periférico foi 640eos/µL (faixa 100-5.100); 200eos/µL (faixa 100-500); e 100 eos/µL (faixa 100-400) em pacientes com AERD, RAP e indivíduos saudáveis, respectivamente (AERD versus RAP, p=0,0003; AERD versus indivíduos saudáveis, p=0,01). A média do número de eosinófilos teciduais foi de 113,3células/CGA; 2,5células/CGA; e 0,7células/CGA, respectivamente (AERD versus RAP, p=0,017; AERD versus indivíduos saudáveis p=0,003). A média geométrica da IgE total foi de 290,18kU/L (faixa 59,5-8.140); 69,96kU/mL (faixa 5,5-898); e 43,14kU/mL (faixa 4- 1.328) em pacientes com AERD, RAP e indivíduos saudáveis, respectivamente, sem diferença entre os grupos. Periostina sérica foi mais elevada em pacientes com AERD quando comparados a indivíduos saudáveis. A mediana de periostina sérica foi de 602ng/ml (faixa 290,7-1.055); 535,6ng/mL (faixa 209-733,2); e 496,7mg/mL (faixa 327,4-713,4), em pacientes com AERD, RAP e indivíduos saudáveis, respectivamente (AERD versus indivíduos saudáveis, p=0,01). Em subgrupo de pacientes brasileiros com AERD, observamos elevado número de eosinófilos em sangue periférico e em tecido, quando comparados a pacientes com RAP e indivíduos saudáveis. Níveis mais elevados de periostina sérica foram observados em pacientes com AERD, quando comparados a indivíduos saudáveis, indicando forte resposta do tipo 2 em pacientes com AERD em nosso meio / Aspirin exacerbated respiratory disease (also known as AERD), is characterized by eosinophilic chronic hypertrophic rhinosinusitis, nasosinusal polyps, asthma and hypersensitivity to Aspirin or other non-steroidal anti-inflammatory drugs. A higher expression of the biomarker periostin has been described in patients with AERD, in nasosinusal tissue, including basal membrane, extracellular matrix and nasal polyps. We evaluated the levels of serum periostin in patients with AERD, and compare those levels with patients with perennial allergic rhinitis (PAR), and with healthy subjects. Twenty-nine patients (20F/9M) with AERD were selected from the Allergy and Otolaryngology Clinics, from the Clinical Hospital of the Ribeirão Preto Medicine School, University of São Paulo (HCFMRP-USP). Those patients underwent confirmatory exams, such as Oral Provocation test with aspirin, and were submitted to polyp biopsy through nasofibroscopy. As a control group, 12 patients (9F/3M) with PAR and 23 healthy subjects (14F/9M) were selected. Eosinophils were quantified in peripheral blood and in polyp tissue or nasal mucosa. Total IgE was determined by ImmunoCAP, and serum periostin was measured by ELISA. The number of tissue eosinophils by high magnification field (HMF), number of eosinophils by cubic milliliter in peripheral blood, total IgE levels and serum periostin levels in patients with AERD were compared with those from patients with PAR and healthy subjects. Patients with AERD were older (median 54 years, and range 22-60) than patients with PAR (median 30 years, range 19-57, p=0,0001) and healthy subjects (median 29 years, range 19-53, p=0,0001), with no difference between genders. The numbers of eosinophils in peripheral blood and in tissue were higher in patients with AERD than patients with PAR or healthy subjects. The median of eosinophil number in peripheral blood was 640eos/µL (range 100-5.100); 200eos/µL (range 100-500); e 100eos/µL (range 100-400) in patients with AERD, PAR and healthy subjects respectively (AERD vs PAR, p=0,0003; AERD vs healthy subjects, p=0,01). The average number of tissue eosinophils was 113,3cels/HMF; 2,5cels/HMF; e 0,7cels/HMF, respectively (AERD vs PAR, p=0,017; AERD vs healthy subjects, p=0,003). The geometric mean for total IgE was 290,18kU/mL (range 59,5-8.140); 69,96kU/mL (range 5,5-898); and 43,14kU/mL (range 4-1.328) in patients with AERD, PAR and healthy subjects respectively, with no difference between the groups. Serum periostin was higher in patients with AERD when compared with healthy subjects. The median for serum periostin was 602ng/ml (range 290,7-1.055); 535,6ng/mL (range 209-733,2); e 496,7ng/mL (range 327,4-713,4), in patients with AERD, PAR and healthy subjects respectively (AERD vs healthy subjects, p=0,01). In a Brazilian subgroup of patients with AERD, we observed an elevated number of eosinophils in peripheral blood and tissue, when compared with patients with PAR and healthy subjects. Higher levels of serum periostin were observed in patients with AERD, when compared with healthy subjects, indicating a strong type 2 response in patients with AERD in our environment.

No description available.

<p>The majority (75%) of renal cell carcinoma (RCC) is comprised of clear cell renal cell carcinoma (ccRCC). Despite ccRCC being the most aggressive form of RCC, our knowledge regarding the pathogenesis of the disease remains limited. We have identified upregulation of the extracellular protein periostin (POSTN) in ccRCC. Western blot analysis of ccRCC tumours from 27 patients demonstrated high POSTN protein expression in 26 tumours compared to their respective adjacent normal kidney tissue (ANK). Immunohistochemistry (IHC) analysis revealed high levels of stromal POSTN protein in the ccRCC primary tumours and 16 metastasized ccRCCs. Intriguingly, abundant stromal POSTN in the tumour and non tumour boundary were observed in local and metastaized ccRCC, and in A498 ccRCC cell-derived xenograft tumours. Collectively, these results suggest that the ccRCC-associated POSTN was derived from the stroma. This notion was supported by the co-existence of POSTN with α-smooth muscle actin (αSMA) in both local and metastasized ccRCC tumours. αSMA is a marker of activated stromal fibroblasts (myofibroblasts). Furthermore, co-culture of NIH3T3 murine fibroblasts with human A498 or 786-0 ccRCC cells dramatically enhanced POSTN transcription and secretion from NIH3T3 cells. Extracellular POSTN significantly enhanced A498 cell attachment. Upregulation of POSTN in NIH3T3 cells enhanced their proliferation. Taken together, my research demonstrates that 1) ccRCC induces fibroblast-mediated accumulation of extracellular POSTN, 2) stromal POSTN enhances ccRCC attachment, and 3) high levels of POSTN promotes fibroblasts' proliferation. These observations suggest a critical role for POSTN in mediating the co-evolving process between ccRCC and its stroma during ccRCC pathogenesis.</p> / Master of Science (MSc)

Les troubles musculo-squelettiques représentent la deuxième cause d'invalidité dans le monde et des millions de personnes subissent une fracture chaque année. Bien que la régénération osseuse soit un processus efficace permettant à l'os de récupérer sa structure et ses fonctions initiales, 10% des fractures ne guérissent pas correctement et peuvent entraîner un retard de régénération ou une non-consolidation osseuse. Le processus de régénération osseuse repose sur l'activation de cellules souches squelettiques (CSS), dont les origines et les mécanismes d'action sont encore mal caractérisés. De nombreuses études se sont concentrées sur les cellules stromales de la moelle osseuse (CSM) comme source principale de CSS pour le processus de régénération osseuse endogène et les thérapies cellulaires. Cependant, notre laboratoire et d'autres équipes ont récemment montré que le périoste est une source majeure de cellules qui contribuent à la formation de cartilage et d’os dans le cal alors que les CSM ont une contribution minimale et restreinte au compartiment de moelle osseuse pendant la régénération. Le but de ce projet est de caractériser les cellules souches squelettiques du périoste et comparer leur potentiel de régénération in vitro et in vivo avec les cellules stromales de la moelle osseuse. Nous avons mis au point des cultures primaires de cellules issues du périoste (CPs) et de la moelle (CSMs) de souris. Les CPs et les CSMs expriment des marqueurs communs et peuvent se différencier dans les trois lignages mésenchymateux (ostéoblastes, adipocytes et chondrocytes) in vitro. In vitro les CPs ont un potentiel clonogénique et une croissance cellulaire plus élevés que les CSMs. Malgré l’origine embryonnaire commune des CPs et CSMs, les CPs n’ont pas les mêmes fonctions aux stades postnatal et adulte. Après transplantation au site de fracture, les CPs ont un meilleur potentiel d’intégration au centre du cal dans le cartilage et l’os comparé aux CSMs. Les CPs persistent dans le cal à long terme et peuvent reconstituer un pool de CPs dans le périoste nouvellement formé après régénération, permettant d’être mobilisées à nouveau après des blessures successives. Par des analyses transcriptomiques des CPs et CSMs isolées avant et après fracture, nous avons caractérisé les profiles moléculaires des CPs et des CSMs et mis en évidence une réponse à la blessure plus importante chez les CPs. Le gène Periostin (Postn) et d’autres gènes codant pour des protéines de la matrice extracellulaire liées à Postn sont surexprimées dans les CPs activées par la fracture. L’expression de POSTN est détectée dans le périoste et dans le cal pendant tout le processus de régénération osseuse. Les souris invalidées pour Postn ont un phénotype de régénération osseuse anormale marqué par la formation de fibrose et une absence de consolidation osseuse. Ce phénotype est dû à une déficience du périoste et des CPs chez les souris Postn mutantes. En absence de Postn, le reconstitution du périoste et du pools de CPs à long terme est abolie entraînant une incapacité du périoste mutant à participer à la réparation osseuse après une seconde blessure. En conclusion, ce travail a mis en évidence que le périoste contient une population de CSS avec un potentiel de régénération élevé pour la réparation osseuse endogène comparé aux CSMs. Nous montrons que Périostine est une protéine clé du périoste, régulant la capacité des CPs à répondre aux blessures et permettant de maintenir l’intégrité du périoste et le pool de CPs à long terme. Le périoste et les cellules souches du périoste pourraient donc être une meilleure cible pour augmenter la régénération osseuse cliniquement. / Musculoskeletal disorders represent the second cause of disability worldwide. Among them, bone repair defects occur in 10% of patients that sustain a fracture causing delayed union or non-union. Bone regeneration is normally an efficient process allowing bone to recover its proper shape and functions, and relying on the activation of skeletal stem cells (SSCs), that are still poorly characterized. Numerous studies have concentrated on bone marrow stromal cells/skeletal stem cells (BMSCs) to understand the role of SSCs in bone regeneration and for cell-based therapies. Recently, our laboratory and others have shown that the periosteum is a major source of cells that contribute to cartilage and bone formation in the fracture callus while BMSC’s contribution to the endogenous repair process is minimal and restricted to the bone marrow compartment. Here, we aimed to characterize skeletal stem cells within periosteum and compare their in vitro and in vivo regenerative potential with BMSCs. We established primary cultures of periosteal cells (PCs) and BMSCs in mice and showed that PCs and BMSCs express similar markers by FACS and qRT-PCR and can differentiate into the three mesenchymal lineages (osteoblasts, adipocytes and chondrocytes) in vitro. We show that although PCs and BMSCs have common embryonic origins, PCs exhibit superior bone regenerative potential in mature bones with higher CFU-F activity, cell growth and migration capacity in vitro compared to BMSCs. By lineage tracing after transplantation at fracture sites in vivo, we show that PCs can better contribute to cartilage and bone and integrate long-term in the callus compared to BMSCs. Using a periosteum graft approach, we show that PCs can repopulate the periosteum after injury and are mobilized again after subsequent injuries to repair bone. Microarray analyses of PCs and BMSCs isolated from intact and injured tibias 3 days post fracture show an enhanced molecular response to injury of PCs. Periostin (Postn) and other genes encoding extracellular matrix (ECM) proteins linked to Postn were up-regulated in activated PCs. Postn expression was detected in the periosteum and the callus through all stages of bone regeneration and Postn deficient mice have impaired bone regeneration leading to fibrosis and non-union. This phenotype is due to a deficient periosteum and PCs as shown by in vitro and in vivo experiments. Moreover, the capacity of PCs to repopulate the newly formed periosteum and contribute to repair after a second injury is abolished in the absence of Periostin. In conclusion, this work shows that periosteum comprises SSCs with high bone regenerative potential for endogenous bone repair compared to BMSCs. We show that Periostin is a key ECM component of the periosteum regulating the ability of PCs to respond to injury, participate in skeletal repair and maintain the pool of PCs in the periosteum. SSCs within periosteum are therefore a promising target to augment bone regeneration clinically.