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Generation of gene-corrected functional osteoclasts from osteopetrotic induced pluripotent stem cells

Xian, Xiaojie LU ; Moraghebi, Roksana LU ; Löfvall, Henrik LU orcid ; Fasth, Anders ; Henriksen, Kim ; Richter, Johan LU ; Woods, Niels Bjarne LU and Moscatelli, Ilana LU (2020) In Stem Cell Research & Therapy 11.
Abstract

BACKGROUND: Infantile malignant osteopetrosis (IMO) is an autosomal recessive disorder characterized by non-functional osteoclasts and a fatal outcome early in childhood. About 50% of patients have mutations in the TCIRG1 gene. METHODS: IMO iPSCs were generated from a patient carrying a homozygous c.11279G>A (IVS18+1) mutation in TCIRG1 and transduced with a lentiviral vector expressing human TCIRG1. Embryoid bodies were generated and differentiated into monocytes. Non-adherent cells were harvested and further differentiated into osteoclasts on bovine bone slices. RESULTS: Release of the bone resorption biomarker CTX-I into the media of gene-corrected osteoclasts was 5-fold higher than that of the uncorrected osteoclasts and 35% of... (More)

BACKGROUND: Infantile malignant osteopetrosis (IMO) is an autosomal recessive disorder characterized by non-functional osteoclasts and a fatal outcome early in childhood. About 50% of patients have mutations in the TCIRG1 gene. METHODS: IMO iPSCs were generated from a patient carrying a homozygous c.11279G>A (IVS18+1) mutation in TCIRG1 and transduced with a lentiviral vector expressing human TCIRG1. Embryoid bodies were generated and differentiated into monocytes. Non-adherent cells were harvested and further differentiated into osteoclasts on bovine bone slices. RESULTS: Release of the bone resorption biomarker CTX-I into the media of gene-corrected osteoclasts was 5-fold higher than that of the uncorrected osteoclasts and 35% of that of control osteoclasts. Bone resorption potential was confirmed by the presence of pits on the bones cultured with gene-corrected osteoclasts, absent in the uncorrected IMO osteoclasts. CONCLUSIONS: The disease phenotype was partially corrected in vitro, providing a valuable resource for therapy development for this form of severe osteopetrosis.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Gene transfer, Infantile malignant osteopetrosis, iPSC generation, Osteoclast differentiation
in
Stem Cell Research & Therapy
volume
11
article number
179
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85084787210
  • pmid:32414402
ISSN
1757-6512
DOI
10.1186/s13287-020-01701-y
language
English
LU publication?
yes
id
b5f46c64-8326-49c1-b163-edca5984240d
date added to LUP
2020-06-16 15:23:11
date last changed
2025-10-14 11:33:56
@article{b5f46c64-8326-49c1-b163-edca5984240d,
  abstract     = {{<p>BACKGROUND: Infantile malignant osteopetrosis (IMO) is an autosomal recessive disorder characterized by non-functional osteoclasts and a fatal outcome early in childhood. About 50% of patients have mutations in the TCIRG1 gene. METHODS: IMO iPSCs were generated from a patient carrying a homozygous c.11279G&gt;A (IVS18+1) mutation in TCIRG1 and transduced with a lentiviral vector expressing human TCIRG1. Embryoid bodies were generated and differentiated into monocytes. Non-adherent cells were harvested and further differentiated into osteoclasts on bovine bone slices. RESULTS: Release of the bone resorption biomarker CTX-I into the media of gene-corrected osteoclasts was 5-fold higher than that of the uncorrected osteoclasts and 35% of that of control osteoclasts. Bone resorption potential was confirmed by the presence of pits on the bones cultured with gene-corrected osteoclasts, absent in the uncorrected IMO osteoclasts. CONCLUSIONS: The disease phenotype was partially corrected in vitro, providing a valuable resource for therapy development for this form of severe osteopetrosis.</p>}},
  author       = {{Xian, Xiaojie and Moraghebi, Roksana and Löfvall, Henrik and Fasth, Anders and Henriksen, Kim and Richter, Johan and Woods, Niels Bjarne and Moscatelli, Ilana}},
  issn         = {{1757-6512}},
  keywords     = {{Gene transfer; Infantile malignant osteopetrosis; iPSC generation; Osteoclast differentiation}},
  language     = {{eng}},
  month        = {{05}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Stem Cell Research & Therapy}},
  title        = {{Generation of gene-corrected functional osteoclasts from osteopetrotic induced pluripotent stem cells}},
  url          = {{http://dx.doi.org/10.1186/s13287-020-01701-y}},
  doi          = {{10.1186/s13287-020-01701-y}},
  volume       = {{11}},
  year         = {{2020}},
}