Self-assembling human skeletal organoids for disease modeling and drug testing.

Skeletal conditions represent a considerable challenge to health systems globally. Barriers to effective therapeutic development include a lack of accurate preclinical tissue and disease models. Most recently, work was attempted to present a novel whole organ approach to modeling human bone and cartilage tissues. These self-assembling skeletal organoids mimic the cellular milieu and extracellular organization present in native tissues. Bone organoids demonstrated osteogenesis and micro vessel formation, and cartilage organoids showed evidence of cartilage development and maturation. Skeletal organoids derived from both bone and cartilage tissues yielded spontaneous polarization of their cartilaginous and bone components. Using these hybrid skeletal organoids, we successfully generated "mini joint" cultures, which we used to model inflammatory disease and test Adenosine (A2A ) receptor agonists as a therapeutic agent. The work and respective results indicated that skeletal organoids can be an effective biological model for tissue development and disease as well as to test therapeutic agents.

[1]  Allon M. Klein,et al.  Inflation-collapse dynamics drive patterning and morphogenesis in intestinal organoids. , 2021, Cell stem cell.

[2]  Benjamin Friedman,et al.  Adenosine A2A receptor signaling promotes FoxO associated autophagy in chondrocytes , 2021, Scientific Reports.

[3]  M. Heim,et al.  Organoids to model liver disease , 2020, JHEP reports : innovation in hepatology.

[4]  A. Qian,et al.  The Bone Extracellular Matrix in Bone Formation and Regeneration , 2020, Frontiers in Pharmacology.

[5]  M. Mckee,et al.  Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018. , 2020, JAMA.

[6]  D. Amanatullah,et al.  Single-cell mass cytometry reveals cross-talk between inflammation-dampening and inflammation-amplifying cells in osteoarthritic cartilage , 2020, Science Advances.

[7]  C. Corciulo,et al.  Signaling of the Purinergic System in the Joint , 2020, Frontiers in Pharmacology.

[8]  Nipha Chaicharoenaudomrung,et al.  Three-dimensional cell culture systems as an in vitro platform for cancer and stem cell modeling , 2019, World journal of stem cells.

[9]  C. Haigh,et al.  Using our mini-brains: cerebral organoids as an improved cellular model for human prion disease , 2019, Neural regeneration research.

[10]  Nicola Elvassore,et al.  Extracellular matrix hydrogel derived from decellularized tissues enables endodermal organoid culture , 2019, Nature Communications.

[11]  Christopher D Lopez,et al.  Local delivery of adenosine receptor agonists to promote bone regeneration and defect healing. , 2019, Advanced drug delivery reviews.

[12]  A. Burlui,et al.  The Link Between Inflammaging and Degenerative Joint Diseases , 2019, International journal of molecular sciences.

[13]  Haniye Sadat Sajadi,et al.  Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017 , 2018, The Lancet.

[14]  H. Z. Wang,et al.  Intercellular communication via gap junction channels between chondrocytes and bone cells. , 2018, Biochimica et biophysica acta. Biomembranes.

[15]  Christopher D Lopez,et al.  The Role of Adenosine Receptor Activation in Attenuating Cartilaginous Inflammation , 2018, Inflammation.

[16]  Nazish Sayed,et al.  Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond , 2018, Development.

[17]  Soo Young Lee,et al.  Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation , 2017, Molecules and cells.

[18]  H. Sebastian Seung,et al.  Trainable Weka Segmentation: a machine learning tool for microscopy pixel classification , 2017, Bioinform..

[19]  Li-Hsin Han,et al.  Modeling Physiological Events in 2D vs. 3D Cell Culture. , 2017, Physiology.

[20]  O. Kennedy,et al.  Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression , 2017, Nature Communications.

[21]  R. Adams,et al.  Regulation of Hematopoiesis and Osteogenesis by Blood Vessel-Derived Signals. , 2016, Annual review of cell and developmental biology.

[22]  Hans Clevers,et al.  Organoids: Modeling Development and the Stem Cell Niche in a Dish. , 2016, Developmental cell.

[23]  C. Helmick,et al.  Updated Projected Prevalence of Self‐Reported Doctor‐Diagnosed Arthritis and Arthritis‐Attributable Activity Limitation Among US Adults, 2015–2040 , 2016, Arthritis & rheumatology.

[24]  P. Cerri,et al.  Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells , 2015, BioMed research international.

[25]  T. Senda,et al.  The osteocyte plays multiple roles in bone remodeling and mineral homeostasis , 2015, Medical Molecular Morphology.

[26]  B. Cronstein,et al.  Direct or indirect stimulation of adenosine A2A receptors enhances bone regeneration as well as bone morphogenetic protein‐2 , 2015, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  Q. Guo,et al.  Bone-cartilage interface crosstalk in osteoarthritis: potential pathways and future therapeutic strategies. , 2014, Osteoarthritis and cartilage.

[28]  D. Ribatti,et al.  Extracellular Matrix Modulates Angiogenesis in Physiological and Pathological Conditions , 2014, BioMed research international.

[29]  K. Lyons,et al.  TGFβ signaling in cartilage development and maintenance. , 2014, Birth defects research. Part C, Embryo today : reviews.

[30]  Qian Wang,et al.  Role of Insulin-Transferrin-Selenium in Auricular Chondrocyte Proliferation and Engineered Cartilage Formation in Vitro , 2014, International journal of molecular sciences.

[31]  Matthew J. Silva,et al.  Skeletal Blood Flow in Bone Repair and Maintenance , 2013, Bone Research.

[32]  F. Auger,et al.  The pivotal role of vascularization in tissue engineering. , 2013, Annual review of biomedical engineering.

[33]  Y. Sasai.  Next-generation regenerative medicine: organogenesis from stem cells in 3D culture. , 2013, Cell stem cell.

[34]  M. Lotz,et al.  Dysregulated FOXO transcription factors in articular cartilage in aging and osteoarthritis. , 2013, Osteoarthritis and cartilage.

[35]  Yoshiki Sasai,et al.  Self-formation of layered neural structures in three-dimensional culture of ES cells , 2012, Current Opinion in Neurobiology.

[36]  Brendon M. Baker,et al.  Deconstructing the third dimension – how 3D culture microenvironments alter cellular cues , 2012, Journal of Cell Science.

[37]  N. Sims,et al.  Intercellular Cross-Talk Among Bone Cells: New Factors and Pathways , 2012, Current Osteoporosis Reports.

[38]  B. Cronstein,et al.  Adenosine A(2A) receptor ligation inhibits osteoclast formation. , 2012, The American journal of pathology.

[39]  F. Pedata,et al.  CGS 21680, an Agonist of the Adenosine (A2A) Receptor, Reduces Progression of Murine Type II Collagen-induced Arthritis , 2011, The Journal of Rheumatology.

[40]  F. Pedata,et al.  CGS 21680, an agonist of the adenosine (A2A) receptor, decreases acute lung inflammation. , 2011, European journal of pharmacology.

[41]  A. Brandl,et al.  Oxidative stress induces senescence in chondrocytes , 2011, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[42]  E. Moran,et al.  FOXO1 modulates osteoblast differentiation. , 2011, Bone.

[43]  D. Zhang,et al.  Osteopontin induces angiogenesis through activation of PI3K/AKT and ERK1/2 in endothelial cells , 2009, Oncogene.

[44]  A. Simpson,et al.  Chondrocyte survival in articular cartilage: the influence of subchondral bone in a bovine model. , 2009, The Journal of bone and joint surgery. British volume.

[45]  C. Pilapil,et al.  Interleukin‐1β and tumor necrosis factor α inhibit chondrogenesis by human mesenchymal stem cells through NF‐κB–dependent pathways , 2009 .

[46]  Z. Bar‐Shavit.  The osteoclast: A multinucleated, hematopoietic‐origin, bone‐resorbing osteoimmune cell , 2007, Journal of cellular biochemistry.

[47]  E. Greer,et al.  FOXO transcription factors at the interface between longevity and tumor suppression , 2005, Oncogene.

[48]  J. Heersche,et al.  Macrophage Colony Stimulating Factor Increases Bone Resorption in Dispersed Osteoclast Cultures by Increasing Osteoclast Size , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[49]  Richard R. Behringer,et al.  Sox9 is required for cartilage formation , 1999, Nature Genetics.

[50]  Q. Sang,et al.  Complex role of matrix metalloproteinases in angiogenesis , 1998, Cell Research.

[51]  E. Bauer,et al.  Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells , 1992, Journal of cellular physiology.

[52]  J. Tyler.  Articular cartilage cultured with catabolin (pig interleukin 1) synthesizes a decreased number of normal proteoglycan molecules. , 1985, The Biochemical journal.