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Mildred C Embree, Mo Chen, Serhiy Pylawka, Danielle Kong, George M Iwaoka, Ivo Kalajzic, Hai Yao, Chancheng Shi, Dongming Sun, Tzong-Jen Sheu, David A Koslovsky, Alia Koch, Jeremy J Mao
Tissue regeneration using stem cell-based transplantation faces many hurdles. Alternatively, therapeutically exploiting endogenous stem cells to regenerate injured or diseased tissue may circumvent these challenges. Here we show resident fibrocartilage stem cells (FCSCs) can be used to regenerate and repair cartilage. We identify FCSCs residing within the superficial zone niche in the temporomandibular joint (TMJ) condyle. A single FCSC spontaneously generates a cartilage anlage, remodels into bone and organizes a haematopoietic microenvironment...
October 10, 2016: Nature Communications
Kei Matsumoto, Sandhya Xavier, Jun Chen, Yujiro Kida, Mark Lipphardt, Reina Ikeda, Annie Gevertz, Mario Caviris, Antonis K Hatzopoulos, Ivo Kalajzic, James Dutton, Brian B Ratliff, Hong Zhao, Zbygniew Darzynkiewicz, Stefan Rose-John, Michael S Goligorsky
: : Accumulation of myofibroblasts is a hallmark of renal fibrosis. A significant proportion of myofibroblasts has been reported to originate via endothelial-mesenchymal transition. We initially hypothesized that exposing myofibroblasts to the extract of endothelial progenitor cells (EPCs) could reverse this transition. Indeed, in vitro treatment of transforming growth factor-β1 (TGF-β1)-activated fibroblasts with EPC extract prevented expression of α-smooth muscle actin (α-SMA); however, it did not enhance expression of endothelial markers...
October 5, 2016: Stem Cells Translational Medicine
Emilie Roeder, Brya G Matthews, Ivo Kalajzic
Advancing our understanding of osteoblast biology and differentiation is critical to elucidate the pathological mechanisms responsible for skeletal diseases such as osteoporosis. Histology and histomorphometry, the classical methods to study osteoblast biology, identify osteoblasts based on their location and morphology and ability to mineralize matrix, but do not clearly define their stage of differentiation. Introduction of visual transgenes into the cells of osteoblast lineage has revolutionized the field and resulted in a paradigm shift that allowed for specific identification and isolation of subpopulations within the osteoblast lineage...
November 2016: Bone
M Ikić Matijašević, D Flegar, N Kovačić, V Katavić, T Kelava, A Šućur, S Ivčević, H Cvija, E Lazić Mosler, I Kalajzić, A Marušić, D Grčević
Our study aimed to determine the functional activity of different osteoclast progenitor (OCP) subpopulations and signals important for their migration to bone lesions, causing local and systemic bone resorption during the course of collagen-induced arthritis in C57BL/6 mice. Arthritis was induced with chicken type II collagen (CII), and assessed by clinical scoring and detection of anti-CII antibodies. We observed decreased trabecular bone volume of axial and appendicular skeleton by histomorphometry and micro-computed tomography as well as decreased bone formation and increased bone resorption rate in arthritic mice in vivo...
December 2016: Clinical and Experimental Immunology
Igor Matic, Brya G Matthews, Xi Wang, Nathaniel A Dyment, Daniel L Worthley, David W Rowe, Danka Grcevic, Ivo Kalajzic
The in vivo origin of bone-producing osteoblasts is not fully defined. Skeletal stem cells, a population of mesenchymal stem cells resident in the bone marrow compartment, are thought to act as osteoprogenitors during growth and adulthood. Quiescent bone lining cells (BLCs) have been suggested as a population capable of activation into mature osteoblasts. These cells were defined by location and their morphology and studies addressing their significance have been hampered by their inaccessibility, and lack of markers that would allow for their identification and tracing...
August 10, 2016: Stem Cells
Ryu Yoshida, Farhang Alaee, Felix Dyrna, Mark S Kronenberg, Peter Maye, Ivo Kalajzic, David W Rowe, Augustus D Mazzocca, Nathaniel A Dyment
: Purpose of this study: To elucidate the origin of cell populations that contribute to rotator cuff healing, we developed a mouse surgical model where a full-thickness, central detachment is created in the supraspinatus. MATERIALS AND METHODS: Three different inducible Cre transgenic mice with Ai9-tdTomato reporter expression (PRG4-9, αSMA-9, and AGC-9) were used to label different cell populations in the shoulder. The defect was created surgically in the supraspinatus...
November 2016: Connective Tissue Research
Brya G Matthews, Elena Torreggiani, Emilie Roeder, Igor Matic, Danka Grcevic, Ivo Kalajzic
Heterotopic ossification (HO) is a pathological process where bone forms in connective tissues such as skeletal muscle. Previous studies have suggested that muscle-resident non-myogenic mesenchymal progenitors are the likely source of osteoblasts and chondrocytes in HO. However, the previously identified markers of muscle-resident osteoprogenitors label up to half the osteoblasts within heterotopic lesions, suggesting other cell populations are involved. We have identified alpha smooth muscle actin (αSMA) as a marker of osteoprogenitor cells in bone and periodontium, and of osteo-chondro progenitors in the periosteum during fracture healing...
March 2016: Bone
Mille Kolind, Justin D Bobyn, Brya G Matthews, Kathy Mikulec, Alastair Aiken, David G Little, Ivo Kalajzic, Aaron Schindeler
To better understand the relative contributions of mesenchymal and endothelial progenitor cells to rhBMP-2 induced bone formation, we examined the distribution of lineage-labeled cells in Tie2-Cre:Ai9 and αSMA-creERT2:Col2.3-GFP:Ai9 reporter mice. Established orthopedic models of ectopic bone formation in the hind limb and spine fusion were employed. Tie2-lineage cells were found extensively in the ectopic bone and spine fusion masses, but co-staining was only seen with tartrate-resistant acid phosphatase (TRAP) activity (osteoclasts) and CD31 immunohistochemistry (vascular endothelial cells), and not alkaline phosphatase (AP) activity (osteoblasts)...
December 2015: Bone
Michael D Prater, Valérie Petit, I Alasdair Russell, Rajshekhar R Giraddi, Mona Shehata, Suraj Menon, Reiner Schulte, Ivo Kalajzic, Nicola Rath, Michael F Olson, Daniel Metzger, Marisa M Faraldo, Marie-Ange Deugnier, Marina A Glukhova, John Stingl
Contractile myoepithelial cells dominate the basal layer of the mammary epithelium and are considered to be differentiated cells. However, we observe that up to 54% of single basal cells can form colonies when seeded into adherent culture in the presence of agents that disrupt actin-myosin interactions, and on average, 65% of the single-cell-derived basal colonies can repopulate a mammary gland when transplanted in vivo. This indicates that a high proportion of basal myoepithelial cells can give rise to a mammary repopulating unit (MRU)...
October 2014: Nature Cell Biology
Maria Krevvata, Barbara C Silva, John S Manavalan, Marta Galan-Diez, Aruna Kode, Brya Grace Matthews, David Park, Chiyuan A Zhang, Naomi Galili, Thomas L Nickolas, David W Dempster, William Dougall, Julie Teruya-Feldstein, Aris N Economides, Ivo Kalajzic, Azra Raza, Ellin Berman, Siddhartha Mukherjee, Govind Bhagat, Stavroula Kousteni
The bone marrow niche is thought to act as a permissive microenvironment required for emergence or progression of hematologic cancers. We hypothesized that osteoblasts, components of the niche involved in hematopoietic stem cell (HSC) function, influence the fate of leukemic blasts. We show that osteoblast numbers decrease by 55% in myelodysplasia and acute myeloid leukemia patients. Further, genetic depletion of osteoblasts in mouse models of acute leukemia increased circulating blasts and tumor engraftment in the marrow and spleen leading to higher tumor burden and shorter survival...
October 30, 2014: Blood
Nathaniel A Dyment, Yusuke Hagiwara, Brya G Matthews, Yingcui Li, Ivo Kalajzic, David W Rowe
Unlike during embryogenesis, the identity of tissue resident progenitor cells that contribute to postnatal tendon growth and natural healing is poorly characterized. Therefore, we utilized 1) an inducible Cre driven by alpha smooth muscle actin (SMACreERT2), that identifies mesenchymal progenitors, 2) a constitutively active Cre driven by growth and differentiation factor 5 (GDF5Cre), a critical regulator of joint condensation, in combination with 3) an Ai9 Cre reporter to permanently label SMA9 and GDF5-9 populations and their progeny...
2014: PloS One
Stefano Zanotti, Ivo Kalajzic, Hector Leonardo Aguila, Ernesto Canalis
Sex and genetic factors determine skeletal mass, and we tested whether bone histomorphometric parameters were sexually dimorphic in femurs from 1 to 6 month old C57BL/6 mice. Trabecular bone volume declined more rapidly in female mice than in male littermates because of enhanced bone resorption. Although bone formation was not different between sexes, female mice exhibited a higher number of osteoblasts than male littermates, suggesting that osteoblasts from female mice may have a reduced ability to form bone...
2014: PloS One
Penelope Pauley, Brya G Matthews, Liping Wang, Nathaniel A Dyment, Igor Matic, David W Rowe, Ivo Kalajzic
PURPOSE: Osteogenesis imperfecta is a serious genetic disorder that results from improper type I collagen production. We aimed to evaluate whether bone marrow stromal cells (BMSC) delivered locally into femurs were able to engraft, differentiate into osteoblasts, and contribute to formation of normal bone matrix in the osteogenesis imperfect murine (oim) model. METHODS: Donor BMSCs from bone-specific reporter mice (Col2.3GFP) were expanded in vitro and transplanted into the femoral intramedullary cavity of oim mice...
September 2014: International Orthopaedics
Brya G Matthews, Danka Grcevic, Liping Wang, Yusuke Hagiwara, Hrvoje Roguljic, Pujan Joshi, Dong-Guk Shin, Douglas J Adams, Ivo Kalajzic
Fracture healing is a regenerative process that involves coordinated responses of many cell types, but characterization of the roles of specific cell populations in this process has been limited. We have identified alpha smooth muscle actin (αSMA) as a marker of a population of mesenchymal progenitor cells in the periosteum that contributes to osteochondral elements during fracture healing. Using a lineage tracing approach, we labeled αSMA-expressing cells, and characterized changes in the periosteal population during the early stages of fracture healing by histology, flow cytometry, and gene expression profiling...
2014: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Elena Torreggiani, Brya G Matthews, Slavica Pejda, Igor Matic, Mark C Horowitz, Danka Grcevic, Ivo Kalajzic
Presently there is no clear evidence for the ability of mature osteogenic lineage cells to dedifferentiate. In order to identify and trace mature osteogenic lineage cells, we have utilized transgenic mouse models in which the dentin matrix protein 1 (Dmp1) promoter drives expression of GFP (active marker) or Cre recombinase (historic label) in preosteocytes/osteocytes. In long bone chip outgrowth cultures, in which cells on the bone surface were enzymatically removed, cells with previous activity of the Dmp1 promoter migrated onto plastic and down-regulated Dmp1-GFP expression...
2013: PloS One
Xin Li, Jamie Garcia, Jinxiu Lu, Sidney Iriana, Ivo Kalajzic, David Rowe, Linda L Demer, Yin Tintut
Bioactive lipids initiate inflammatory reactions leading to pathogenesis of atherosclerosis. Evidence shows that they also contribute to bone loss by inhibiting parathyroid hormone receptor (PTH1R) expression and differentiation of osteoblasts. We previously demonstrated that bone anabolic effects of PTH(1-34) are blunted in hyperlipidemic mice and that these PTH effects are restored by antioxidants. However, it is not clear which osteoblastic cell developmental stage is targeted by bioactive lipids. To investigate the effects of hyperlipidemia at the cellular level, hyperlipidemic Ldlr(-/-) mice were bred with Col3...
January 2014: Journal of Cellular Biochemistry
Wuchen Yang, Dayong Guo, Marie A Harris, Yong Cui, Jelica Gluhak-Heinrich, Junjie Wu, Xiao-Dong Chen, Charles Skinner, Jeffry S Nyman, James R Edwards, Gregory R Mundy, Alex Lichtler, Barbara E Kream, David W Rowe, Ivo Kalajzic, Val David, Darryl L Quarles, Demetri Villareal, Greg Scott, Manas Ray, S Liu, James F Martin, Yuji Mishina, Stephen E Harris
We generated a new Bmp2 conditional-knockout allele without a neo cassette that removes the Bmp2 gene from osteoblasts (Bmp2-cKO(ob)) using the 3.6Col1a1-Cre transgenic model. Bones of Bmp2-cKO(ob) mice are thinner, with increased brittleness. Osteoblast activity is reduced as reflected in a reduced bone formation rate and failure to differentiate to a mature mineralizing stage. Bmp2 in osteoblasts also indirectly controls angiogenesis in the periosteum and bone marrow. VegfA production is reduced in Bmp2-cKO(ob) osteoblasts...
September 15, 2013: Journal of Cell Science
Dario Repic, Elena Torreggiani, Tiziana Franceschetti, Brya G Matthews, Sanja Ivcevic, Alexander C Lichtler, Danka Grcevic, Ivo Kalajzic
Previous studies reported that embryonic stem cells (ESCs) can be induced to differentiate into cells showing a mature osteoblastic phenotype by culturing them under osteo-inductive conditions. It is probable that osteogenic differentiation requires that ESCs undergo differentiation through an intermediary step involving a mesenchymal lineage precursor. Based on our previous studies indicating that adult mesenchymal progenitor cells express α-smooth muscle actin (αSMA), we have generated ESCs from transgenic mice in which an αSMA promoter directs the expression of red fluorescent protein (RFP) to mesenchymal progenitor cells...
2013: Connective Tissue Research
Ivo Kalajzic, Brya G Matthews, Elena Torreggiani, Marie A Harris, Paola Divieti Pajevic, Stephen E Harris
Osteocytes, the most abundant cell population of the bone lineage, have been a major focus in the bone research field in recent years. This population of cells that resides within mineralized matrix is now thought to be the mechanosensory cell in bone and plays major roles in the regulation of bone formation and resorption. Studies of osteocytes had been impaired by their location, resulting in numerous attempts to isolate primary osteocytes and to generate cell lines representative of the osteocytic phenotype...
June 2013: Bone
Sandra Jastrzebski, Judith Kalinowski, Marina Stolina, Faryal Mirza, Elena Torreggiani, Ivo Kalajzic, Hee Yeon Won, Sun-Kyeong Lee, Joseph Lorenzo
We examined the effects that ovariectomy had on sclerostin mRNA and protein levels in the bones of 8-week-old mice that were either sham-operated (SHAM) or ovariectomized (OVX) and then euthanized 3 or 6 weeks later. In this model, bone loss occurred between 3 and 5 weeks postsurgery. In calvaria, ovariectomy significantly decreased sclerostin mRNA levels at 6 weeks postsurgery (by 52%) but had no significant effect at 3 weeks. In contrast, sclerostin mRNA levels were significantly lower in OVX femurs at 3 weeks postsurgery (by 53%) but equal to that of SHAM at 6 weeks...
March 2013: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
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