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The Use of Patient-Specific Induced Pluripotent Stem Cells (iPSCs) to Identify Osteoclast Defects in Rare Genetic Bone Disorders.

Chen IP - J Clin Med (2014)

Bottom Line: Challenges for studying these bone diseases come from a lack of suitable animal models and unavailability of skeletal tissues for studies.Patient-specific induced pluripotent stem cells (iPSCs) can be generated from somatic cells of various tissue sources and in theory can be differentiated into any desired cell type.Our group focuses on the use of human iPSCs (hiPSCs) to identify osteoclast defects in craniometaphyseal dysplasia.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oral Health and Diagnostic Sciences, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA; ipchen@uchc.edu ; Tel.: +1-860-679-1030.

ABSTRACT
More than 500 rare genetic bone disorders have been described, but for many of them only limited treatment options are available. Challenges for studying these bone diseases come from a lack of suitable animal models and unavailability of skeletal tissues for studies. Effectors for skeletal abnormalities of bone disorders may be abnormal bone formation directed by osteoblasts or anomalous bone resorption by osteoclasts, or both. Patient-specific induced pluripotent stem cells (iPSCs) can be generated from somatic cells of various tissue sources and in theory can be differentiated into any desired cell type. However, successful differentiation of hiPSCs into functional bone cells is still a challenge. Our group focuses on the use of human iPSCs (hiPSCs) to identify osteoclast defects in craniometaphyseal dysplasia. In this review, we describe the impact of stem cell technology on research for better treatment of such disorders, the generation of hiPSCs from patients with rare genetic bone disorders and current protocols for differentiating hiPSCs into osteoclasts.

No MeSH data available.


Related in: MedlinePlus

Summary of generating osteoclasts from human iPSCs.
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Figure 1: Summary of generating osteoclasts from human iPSCs.

Mentions: A preferred strategy for studying defective osteoclastogenesis in rare genetic bone disorders using patient-specific hiPSCs is summarized in Figure 1. One challenge of hiPSC disease modeling in vitro is the lack of genetically matched controls. Using healthy subjects as controls may not be the best solution as individual hESCs and hiPSC lines differentiate to specific cell populations with variable efficiency because of biological variability [98]. Distinguishing mutation-relevant disease phenotypes from genetic/epigenetic variations becomes easier in isogenic hiPSCs, which only differ at disease-causing mutations. Correction or introduction of specific mutations into a cell can be achieved by genome editing using zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) or the clustered regulatory interspaced short palindromic repeats/Cas9 system (CRISPR) [99–102]. Using step-wise OC differentiation protocols for differentiating hESCs or hiPSCs may allow researchers to identify which step of osteoclastogenesis is disrupted by a disease causing mutation. Analysis tools are available to study each step (lineage determination of precursors, precursor proliferation, fusion to multinucleated syncytia, maturation to functional osteoclasts) such as expression of marker genes, numbers of TRAP+ mono/multinucleated cells, resorption efficiency, live-image migration assays and nuclear localization of NFATc1. Therapeutic strategies can be investigated once the pathologic mechanisms are understood.


The Use of Patient-Specific Induced Pluripotent Stem Cells (iPSCs) to Identify Osteoclast Defects in Rare Genetic Bone Disorders.

Chen IP - J Clin Med (2014)

Summary of generating osteoclasts from human iPSCs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4300535&req=5

Figure 1: Summary of generating osteoclasts from human iPSCs.
Mentions: A preferred strategy for studying defective osteoclastogenesis in rare genetic bone disorders using patient-specific hiPSCs is summarized in Figure 1. One challenge of hiPSC disease modeling in vitro is the lack of genetically matched controls. Using healthy subjects as controls may not be the best solution as individual hESCs and hiPSC lines differentiate to specific cell populations with variable efficiency because of biological variability [98]. Distinguishing mutation-relevant disease phenotypes from genetic/epigenetic variations becomes easier in isogenic hiPSCs, which only differ at disease-causing mutations. Correction or introduction of specific mutations into a cell can be achieved by genome editing using zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) or the clustered regulatory interspaced short palindromic repeats/Cas9 system (CRISPR) [99–102]. Using step-wise OC differentiation protocols for differentiating hESCs or hiPSCs may allow researchers to identify which step of osteoclastogenesis is disrupted by a disease causing mutation. Analysis tools are available to study each step (lineage determination of precursors, precursor proliferation, fusion to multinucleated syncytia, maturation to functional osteoclasts) such as expression of marker genes, numbers of TRAP+ mono/multinucleated cells, resorption efficiency, live-image migration assays and nuclear localization of NFATc1. Therapeutic strategies can be investigated once the pathologic mechanisms are understood.

Bottom Line: Challenges for studying these bone diseases come from a lack of suitable animal models and unavailability of skeletal tissues for studies.Patient-specific induced pluripotent stem cells (iPSCs) can be generated from somatic cells of various tissue sources and in theory can be differentiated into any desired cell type.Our group focuses on the use of human iPSCs (hiPSCs) to identify osteoclast defects in craniometaphyseal dysplasia.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oral Health and Diagnostic Sciences, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA; ipchen@uchc.edu ; Tel.: +1-860-679-1030.

ABSTRACT
More than 500 rare genetic bone disorders have been described, but for many of them only limited treatment options are available. Challenges for studying these bone diseases come from a lack of suitable animal models and unavailability of skeletal tissues for studies. Effectors for skeletal abnormalities of bone disorders may be abnormal bone formation directed by osteoblasts or anomalous bone resorption by osteoclasts, or both. Patient-specific induced pluripotent stem cells (iPSCs) can be generated from somatic cells of various tissue sources and in theory can be differentiated into any desired cell type. However, successful differentiation of hiPSCs into functional bone cells is still a challenge. Our group focuses on the use of human iPSCs (hiPSCs) to identify osteoclast defects in craniometaphyseal dysplasia. In this review, we describe the impact of stem cell technology on research for better treatment of such disorders, the generation of hiPSCs from patients with rare genetic bone disorders and current protocols for differentiating hiPSCs into osteoclasts.

No MeSH data available.


Related in: MedlinePlus