Fetal Mesenchymal Stem-Cell Engraftment in Bone after In Utero Transplantation in a Patient with Severe Osteogenesis Imperfecta

Blanc, Katarina Le; Götherström, Cecilia; Ringdén, Olle; Hassan, Manal M.; McMahon, Robert P.; Horwitz, Edwin M.; Annerén, Göran; Axelssön, Ove; Nunn, Janice; Ewald, Uwe; Nordén‐Lindeberg, Solveig; Jansson, Monika; Dalton, Ann; Albrecht, Eva; Westgren, Magnus

doi:10.1097/01.tp.0000159029.48678.93

Cited by 417 publications

(304 citation statements)

References 44 publications

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“…Thus, for clinically significant OI caused by structural defects in collagen, suppression of the Mut allele could in principle convert severe types III and IV to the minimally symptomatic OI type I, a situation particularly favorable to therapeutic strategies based on gene silencing. The promising preliminary data on stem cell transplantation in both murine models [18][19][20] and human OI 21,22 contributes to an appealing possibility for correcting the patient's own stem cells in vitro, and transplanting them back to the patient, after checking chromosomal rearrangements 23 or off-target effects 24 in vitro.…”

Section: Introductionmentioning

confidence: 99%

Allele-specific Col1a1 silencing reduces mutant collagen in fibroblasts from Brtl mouse, a model for classical osteogenesis imperfecta

et al. 2013

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Gene silencing approaches have the potential to become a powerful curative tool for a variety of monogenic diseases caused by gain-of-function mutations. Classical osteogenesis imperfecta (OI), a dominantly inherited bone dysplasia, is characterized in its more severe forms by synthesis of structurally abnormal type I collagen, which exerts a negative effect on extracellular matrix. Specific suppression of the mutant (Mut) allele would convert severe OI forms to the mild type caused by a quantitative defect in normal collagen. Here, we describe the in vitro and ex vivo investigation of a small interfering RNA (siRNA) approach to allele-specific gene silencing using Mut Col1a1 from the Brtl mouse, a well-characterized model for classical human OI. A human embryonic kidney cell line, which expresses the firefly luciferase gene, combined with either wild-type or Mut Brtl Col1a1 exon 23 sequences, was used for the first screening. The siRNAs selected based on their specificity and the corresponding short hairpin RNAs (shRNAs) subcloned in a lentiviral vector were evaluated ex vivo in Brtl fibroblasts for their effect on collagen transcripts and protein. A preferential reduction of the Mut allele of up to 52% was associated with about 40% decrease of the Mut protein, with no alteration of cell proliferation. Interestingly, a downregulation of HSP47, a specific collagen chaperone known to be upregulated in some OI cases, was detected. Our data support further testing of shRNAs and their delivery by lentivirus as a strategy to specifically suppress the Mut allele in mesenchymal stem cells of OI patients for autologous transplantation.

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Section: Introductionmentioning

confidence: 99%

Allele-specific Col1a1 silencing reduces mutant collagen in fibroblasts from Brtl mouse, a model for classical osteogenesis imperfecta

et al. 2013

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“…Cell therapy for OI holds much promise, with most studies showing beneficial effects. In humans, whole bone marrow and bone marrow mesenchymal stem cells (MSC) have been transplanted in OI children with gains in body length and bone mineralization [8,9], while allogeneic fetal liver-derived stem cells transplanted in utero led to apparent phenotypic improvement in an OI fetus, although confounded by concomitant bisphosphonate use [10]. In rodent OI models, transplantation of whole bone marrow/bone marrow MSC led to increased collagen content [11], improved bone strength, reduced perinatal lethality [12], and increased osteoblast differentiation [13,14].…”

Section: Introductionmentioning

confidence: 99%

Potential of Human Fetal Chorionic Stem Cells for the Treatment of Osteogenesis Imperfecta

Jones

Moschidou

Abdulrazzak

et al. 2014

Stem Cells and Development

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Osteogenesis imperfecta (OI) is a genetic bone pathology with prenatal onset, characterized by brittle bones in response to abnormal collagen composition. There is presently no cure for OI. We previously showed that human first trimester fetal blood mesenchymal stem cells (MSCs) transplanted into a murine OI model (oim mice) improved the phenotype. However, the clinical use of fetal MSC is constrained by their limited number and low availability. In contrast, human fetal early chorionic stem cells (e-CSC) can be used without ethical restrictions and isolated in high numbers from the placenta during ongoing pregnancy. Here, we show that intraperitoneal injection of e-CSC in oim neonates reduced fractures, increased bone ductility and bone volume (BV), increased the numbers of hypertrophic chondrocytes, and upregulated endogenous genes involved in endochondral and intramembranous ossification. Exogenous cells preferentially homed to long bone epiphyses, expressed osteoblast genes, and produced collagen COL1A2. Together, our data suggest that exogenous cells decrease bone brittleness and BV by directly differentiating to osteoblasts and indirectly stimulating host chondrogenesis and osteogenesis. In conclusion, the placenta is a practical source of stem cells for the treatment of OI.

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“…For bone formation, this has been shown in the pioneer study by Horwitz et al 24,25 as well as by intrauterine transplantation of MSCs in a fetus with osteogenesis imperfecta. On the basis of these observations, we hypothesized that bone repair may be even more efficient in the case of focal lesions, when MSCs can be applied directly and issues of extravasation, migration and homing can be reduced.…”

Section: Cell Lysis Supernatantmentioning

confidence: 95%

“…[21][22][23] Successful systemic application of MSC in children for metabolic bone disorders such as osteogenesis imperfecta prompted us to explore biological properties of MSCs with regard to AVN. 24,25 In particular, we sought for secreted factors modulating the hypoxic and inflammatory environment, which seems equally important as transdifferentiation of MSCs. 26 On the one hand angiogenic factors, for example, vascular endothelialderived growth factor (VEGF), are of crucial importance for tissue regeneration at the site of AVN.…”

Section: Introductionmentioning

confidence: 99%

Secretion of angiogenic proteins by human multipotent mesenchymal stromal cells and their clinical potential in the treatment of avascular osteonecrosis

et al. 2008

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Osteonecrosis is a frequent complication after treatment for childhood leukemia and other steroid-based therapies. The success rate of core decompression surgery is limited. Therefore, we evaluated relevant biological characteristics of human multipotent mesenchymal stromal cells (MSCs) in vitro. MSCs cultured under low-oxygen tensions showed decreased proliferation and differentiation into bone. However, these MSCs secreted significant amounts of vascular endothelial-derived factor in the presence of interferon-c. These in vitro results with potential effects on neovascularization and bone regeneration as well as findings in animal models prompted us to treat five patients with steroid-induced osteonecrosis of the femur by core decompression surgery and instillation of expanded autologous MSCs. Within 3 weeks of culture, sufficient numbers of MSCs were generated using animal protein-free culture conditions. No chromosomal aberrations were detected by matrix-based comparative genomic hybridization. Application of MSCs during core decompression was feasible and safe. Median follow-up is 16 months and the patients in this pilot study reported clinical improvement. Formation of mineralized bone in the osteonecrotic cavity was proven by computed tomography. Taken together, MSCs display biological properties that may add to the efficiency of surgical treatment in osteonecrosis and should be evaluated in larger patient cohorts.

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Fetal Mesenchymal Stem-Cell Engraftment in Bone after In Utero Transplantation in a Patient with Severe Osteogenesis Imperfecta

Abstract: The authors' findings show that allogeneic fetal MSC can engraft and differentiate into bone in a human fetus even when the recipient is immunocompetent and HLA-incompatible.

Cited by 417 publications

References 44 publications

Allele-specific Col1a1 silencing reduces mutant collagen in fibroblasts from Brtl mouse, a model for classical osteogenesis imperfecta

Allele-specific Col1a1 silencing reduces mutant collagen in fibroblasts from Brtl mouse, a model for classical osteogenesis imperfecta

Potential of Human Fetal Chorionic Stem Cells for the Treatment of Osteogenesis Imperfecta

Secretion of angiogenic proteins by human multipotent mesenchymal stromal cells and their clinical potential in the treatment of avascular osteonecrosis

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