Intrauterine transplantation of human fetal mesenchymal stem cells from first-trimester blood repairs bone and reduces fractures in osteogenesis imperfecta mice

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1717-1725 ◽  
Author(s):  
Pascale V. Guillot ◽  
Oyebode Abass ◽  
J. H. Duncan Bassett ◽  
Sandra J. Shefelbine ◽  
George Bou-Gharios ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Osteogenesis Imperfecta ◽  
Bone Fractures ◽  
First Trimester ◽  
Long Bone ◽  
Structural Protein ◽  
Plate Height ◽  
Multiple Fractures ◽  
Donor Cells

Abstract The inherited skeletal dysplasia osteogenesis imperfecta (OI) results in multiple fractures and is currently treated empirically. We transplanted human first-trimester fetal blood mesenchymal stem cells (MSCs) into homozygous oim mice in utero. This resulted in a two-thirds reduction in long bone fractures (P < .01), with fewer fractures per mouse (median 1, range 0-2 in mice that received transplants vs median 3, range 1-5 in mice that did not receive transplants by 12 weeks, P < .01). Nearly all mice that did not receive transplants had fractures (47 [97.9%] of 48), in contrast to 17 (58.6%) of 29 4- to 12-week-old mice that received transplants (P < .01). Transplantation was associated with increased bone strength (P < .01), thickness (P < .01), and length (P < .01), and normalization/reduction of growth plate height in 4- to 12-week-old oim was reduced in mice that underwent transplantion (P < .001). More donor cells were found in bone tissues compared with other organs (P < .001), with cells clustered in areas of active bone formation and remodeling, and at sites of fracture healing. Donor cells found in the bone expressed osteoblast lineage genes, and produced the extracellular bone structural protein osteopontin. Finally, MSC transplantation decreased bone hydroxyproline content. In conclusion, intrauterine transplantation of fetal MSCs markedly reduced fracture rates and skeletal abnormalities in a mouse model of the intermediate severity type III OI, suggesting a scientific basis for MSC treatment of affected human fetuses.

scholarly journals Expanding the phenotype of SPARC-related osteogenesis imperfecta: clinical findings in two patients with pathogenic variants in SPARC and literature review

2021 ◽  
pp. jmedgenet-2021-107942
Author(s):  
Anna Durkin ◽  
Catherine DeVile ◽  
Paul Arundel ◽  
Mary Bull ◽  
Jennifer Walsh ◽  
...  
Keyword(s):  
White Matter ◽  
Osteogenesis Imperfecta ◽  
Motor Development ◽  
Bone Fractures ◽  
Brain Mri ◽  
Subcortical White Matter ◽  
Clinical Findings ◽  
Long Bone ◽  
Vertebral Compression Fractures ◽  
Multiple Fractures

BackgroundSecreted protein, acidic, cysteine rich (SPARC)-related osteogenesis imperfecta (OI), also referred to as OI type XVII, was first described in 2015, since then there has been only one further report of this form of OI. SPARC is located on chromosome 5 between bands q31 and q33. The encoded protein is necessary for calcification of the collagen in bone, synthesis of extracellular matrix and the promotion of changes to cell shape.MethodsWe describe a further two patients with previously unreported homozygous SPARC variants with OI: one splice site; one nonsense pathogenic variant. We present detailed information on the clinical and radiological phenotype and correlate this with their genotype. There are only two previous reports by Mendozo-Londono et al and Hayat et al with clinical descriptions of patients with SPARC variants.ResultsFrom the data we have obtained, common clinical features in individuals with OI type XVII caused by SPARC variants include scoliosis (5/5), vertebral compression fractures (5/5), multiple long bone fractures (5/5) and delayed motor development (3/3). Interestingly, 2/4 patients also had abnormal brain MRI, including high subcortical white matter changes, abnormal fluid-attenuated inversion in the para-atrial white matter and a large spinal canal from T10 to L1. Of significance, both patients reported here presented with significant neuromuscular weakness prompting early workup.ConclusionCommon phenotypic expressions include delayed motor development with neuromuscular weakness, scoliosis and multiple fractures. The data presented here broaden the phenotypic spectrum establishing similar patterns of neuromuscular presentation with a presumed diagnosis of ‘myopathy’.

Long bone mesenchymal stem cells (Lb-MSCs): clinically reliable cells for osteo-diseases

2017 ◽  
Vol 18 (4) ◽  
pp. 489-500 ◽  
Author(s):  
Shirin Toosi ◽  
Hojjat Naderi-Meshkin ◽  
Fatemeh Kalalinia ◽  
Mohammad Taghi Pievandi ◽  
Hossein Hosseinkhani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Long Bone ◽  
Bone Mesenchymal Stem Cells

Gene expression profiling of bone marrow mesenchymal stem cells from Osteogenesis Imperfecta patients during osteoblast differentiation

2017 ◽  
Vol 60 (6) ◽  
pp. 326-334 ◽  
Author(s):  
Carla Martins Kaneto ◽  
Patrícia S. Pereira Lima ◽  
Karen Lima Prata ◽  
Jane Lima dos Santos ◽  
João Monteiro de Pina Neto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Osteogenesis Imperfecta ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Osteoblast Differentiation ◽  
Marrow Mesenchymal Stem Cells

scholarly journals Mesenchymal Stem Cells Coated with Synthetic Bone-Targeting Polymers Enhance Osteoporotic Bone Fracture Regeneration

2020 ◽  
Vol 7 (4) ◽  
pp. 125
Author(s):  
Yuliya Safarova (Yantsen) ◽  
Farkhad Olzhayev ◽  
Bauyrzhan Umbayev ◽  
Andrey Tsoy ◽  
Gonzalo Hortelano ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bone Density ◽  
Active Sites ◽  
Bone Fractures ◽  
Bone Fragility ◽  
Female Rats ◽  
Osteoporotic Bone ◽  
Osteoblast Progenitor ◽  
Osteoclastic Activity

Osteoporosis is a progressive skeletal disease characterized by reduced bone density leading to bone fragility and an elevated risk of bone fractures. In osteoporotic conditions, decrease in bone density happens due to the augmented osteoclastic activity and the reduced number of osteoblast progenitor cells (mesenchymal stem cells, MSCs). We investigated a new method of cell therapy with membrane-engineered MSCs to restore the osteoblast progenitor pool and to inhibit osteoclastic activity in the fractured osteoporotic bones. The primary active sites of the polymer are the N-hydroxysuccinimide and bisphosphonate groups that allow the polymer to covalently bind to the MSCs’ plasma membrane, target hydroxyapatite molecules on the bone surface and inhibit osteolysis. The therapeutic utility of the membrane-engineered MSCs was investigated in female rats with induced estrogen-dependent osteoporosis and ulnar fractures. The analysis of the bone density dynamics showed a 27.4% and 21.5% increase in bone density at 4 and 24 weeks after the osteotomy of the ulna in animals that received four transplantations of polymer-modified MSCs. The results of the intravital observations were confirmed by the post-mortem analysis of histological slices of the fracture zones. Therefore, this combined approach that involves polymer and cell transplantation shows promise and warrants further bio-safety and clinical exploration.

First-trimester human decidua contains a population of mesenchymal stem cells

2010 ◽  
Vol 93 (1) ◽  
pp. 210-219 ◽  
Author(s):  
Rumen Dimitrov ◽  
Dobroslav Kyurkchiev ◽  
Tanya Timeva ◽  
Maria Yunakova ◽  
Maria Stamenova ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
First Trimester ◽  
Human Decidua

scholarly journals Gene Targeting of Mutant COL1A2 Alleles in Mesenchymal Stem Cells From Individuals With Osteogenesis Imperfecta

2008 ◽  
Vol 16 (1) ◽  
pp. 187-193 ◽  
Author(s):  
Joel R Chamberlain ◽  
David R Deyle ◽  
Ulrike Schwarze ◽  
Peirong Wang ◽  
Roli K Hirata ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Osteogenesis Imperfecta ◽  
Gene Targeting

257 EXPRESSION OF DEVELOPMENTAL GENES IN PORCINE NUCLEAR TRANSFER EMBRYOS RECONSTRUCTED WITH BONE MARROW MESENCHYMAL STEM CELLS

2006 ◽  
Vol 18 (2) ◽  
pp. 236
Author(s):  
B. Mohana Kumar ◽  
H.-F. Jin ◽  
J.-G. Kim ◽  
S. Balasubramanian ◽  
S.-Y. Choe ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Nuclear Transfer ◽  
Expression Profiles ◽  
Donor Cells ◽  
Fetal Fibroblasts ◽  
Marrow Mesenchymal Stem Cells

Abnormal gene expression is frequently observed in nuclear transfer (NT) embryos and is one of the suggested causes of the low success rates of this approach. Recent study has suggested that adult stem cells may be better donor cells for NT, as their less differentiated state may ease epigenetic reprogramming by the oocyte (Kato et al. 2004 Biol. Reprod. 70, 415-418). In the present study, we investigated the expression profile of some selected genes involved in the development of the pre-implantation embryos of in vivo- and NT-derived origin using bone marrow mesenchymal stem cells (MSCs) and porcine fetal fibroblasts (pFF) as donors. Isolated population of MSCs from porcine bone marrow were characterized by cell-surface antigen profile (CD13pos, CD105pos, CD45neg, and CD133neg) and by their extensive consistent differentiation to multiple mesenchymal lineages (adipocytic, osteocytic and chondrocytic) under controlled in vitro conditions (Pittenger et al. 1999 Science 284, 143-147). Primary cultures of pFF from a female fetus at <30 days of gestation were established. for NT, donor cells at 3-4 passages were employed. Embryos cloned from MSCs showed enhanced developmental potential compared to pFF cloned embryos, indicated by higher rates of blastocyst formation (15.3% � 4.8 and 9.0% � 3.9, respectively) and total cell number (31.5 � 7.2 and 20.5 � 5.4, respectively) in Day 7 blastocysts. Total RNA was extracted from pools (triplicates) of 10 embryos each of 8-cell, morula, and blastocyst stages of in vivo and NT origin using Dynabeads� mRNA DIRECT" kit (Dynal, Oslo, Norway). Reverse transcription was performed with a Superscript" III cDNA synthesis kit (Invitrogen, Carlsbad, CA, USA). Real-time PCR was performed on a Light cycler� using FastStart DNA Master SYBR Green I (Roche Diagnostics, Mannheim, Germany). The expression profiles of genes involved in transcription (Oct-4, Stat3), DNA methylation (Dnmt1), de novo methylation (Dnmt3a), histone deacetylation (Hdac2), anti-apoptosis (Bcl-xL), and embryonic growth (Igf2r) were determined. The mRNA of H2a was employed to normalize the levels. Significant differences (P < 0.05) in the relative abundance of Stat3, Dnmt1, Dnmt3a, Bcl2, and Igf2r were observed in pFF NT embryos compared with in vivo-produced embryos, whereas embryos derived from MSCs showed expression patterns similar to those of in vivo-produced embryos. However, Oct-4 and Hdac2 revealed similar expression profiles in NT- and in vivo-produced embryos. These results indicate that MSC-derived NT embryos had enhanced embryonic development and their gene expression pattern more closely resembled that of in vivo-produced embryos. Hence, less differentiated MSCs may have a more flexible potential in improving the efficiency of the porcine NT technique. This work was supported by Grant No. R05-2004-000-10702-0 from KOSEF, Republic of Korea.

scholarly journals Amygdalin Promotes Fracture Healing through TGF-β/Smad Signaling in Mesenchymal Stem Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Jun Ying ◽  
Qinwen Ge ◽  
Songfeng Hu ◽  
Cheng Luo ◽  
Fengyi Lu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Fracture Healing ◽  
Bone Fracture ◽  
Transforming Growth Factor ◽  
Bone Fractures ◽  
Conditional Knockout ◽  
Mesenchymal Progenitor Cells ◽  
Bone Fracture Healing ◽  
Smad Signaling

Chondrogenesis and subsequent osteogenesis of mesenchymal stem cells (MSCs) and angiogenesis at injured sites are crucial for bone fracture healing. Amygdalin, a cyanogenic glycoside compound derived from bitter apricot kernel, has been reported to inhibit IL-1β-induced chondrocyte degeneration and to stimulate blood circulation, suggesting a promising role of amygdalin in fracture healing. In this study, tibial fractures in C57BL/6 mice were treated with amygdalin. Fracture calluses were then harvested and subjected to radiographic, histological, and biomechanical testing, as well as angiography and gene expression analyses to evaluate fracture healing. The results showed that amygdalin treatment promoted bone fracture healing. Further experiments using MSC-specific transforming growth factor- (TGF-) β receptor 2 conditional knockout (KO) mice (Tgfbr2Gli1-Cre) and C3H10 T1/2 murine mesenchymal progenitor cells showed that this effect was mediated through TGF-β/Smad signaling. We conclude that amygdalin could be used as an alternative treatment for bone fractures.

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