Defective Proliferation and Osteogenic Potential with Altered Immunoregulatory phenotype of Native Bone marrow-Multipotential Stromal Cells in Atrophic Fracture Non-Union

AbstractBone marrow-Multipotential stromal cells (BM-MSCs) are increasingly used to treat complicated fracture healing e.g., non-union. Though, the quality of these autologous cells is not well characterized. We aimed to evaluate bone healing-related capacities of non-union BM-MSCs. Iliac crest-BM was aspirated from long-bone fracture patients with normal healing (U) or non-united (NU). Uncultured (native) CD271highCD45low cells or passage-zero cultured BM-MSCs were analyzed for gene expression levels, and functional assays were conducted using culture-expanded BM-MSCs. Blood samples were analyzed for serum cytokine levels. Uncultured NU-CD271highCD45low cells significantly expressed fewer transcripts of growth factor receptors, EGFR, FGFR1, and FGRF2 than U cells. Significant fewer transcripts of alkaline phosphatase (ALPL), osteocalcin (BGLAP), osteonectin (SPARC) and osteopontin (SPP1) were detected in NU-CD271highCD45low cells. Additionally, immunoregulation-related markers were differentially expressed between NU- and U-CD271highCD45low cells. Interestingly, passage-zero NU BM-MSCs showed low expression of immunosuppressive mediators. However, culture-expanded NU and U BM-MSCs exhibited comparable proliferation, osteogenesis, and immunosuppression. Serum cytokine levels were found similar for NU and U groups. Collectively, native NU-BM-MSCs seemed to have low proliferative and osteogenic capacities; therefore, enhancing their quality should be considered for regenerative therapies. Further research on distorted immunoregulatory molecules expression in BM-MSCs could potentially benefit the prediction of complicated fracture healing.

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Osteogenic Potential of Mandibular vs. Long-bone Marrow Stromal Cells

Journal of Dental Research ◽

10.1177/0022034510378427 ◽

2010 ◽

Vol 89 (11) ◽

pp. 1293-1298 ◽

Cited By ~ 82

Author(s):

T.L. Aghaloo ◽

T. Chaichanasakul ◽

O. Bezouglaia ◽

B. Kang ◽

R. Franco ◽

...

Keyword(s):

Bone Marrow ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Marrow Stromal Cells ◽

Long Bone ◽

Osteogenic Potential

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Administration of Human Non-Diabetic Mesenchymal Stromal Cells to a Murine Model of Diabetic Fracture Repair: A Pilot Study

Cells ◽

10.3390/cells9061394 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1394

Author(s):

Luke Watson ◽

Xi Zhe Chen ◽

Aideen E. Ryan ◽

Áine Fleming ◽

Aoife Carbin ◽

...

Keyword(s):

Bone Marrow ◽

Pilot Study ◽

Fracture Healing ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Flexural Modulus ◽

Human Mscs ◽

Mineral Density ◽

Non Union ◽

Increased Risk

Individuals living with type 1 diabetes mellitus may experience an increased risk of long bone fracture. These fractures are often slow to heal, resulting in delayed reunion or non-union. It is reasonable to theorize that the underlying cause of these diabetes-associated osteopathies is faulty repair dynamics as a result of compromised bone marrow progenitor cell function. Here it was hypothesized that the administration of non-diabetic, human adult bone marrow-derived mesenchymal stromal cells (MSCs) would enhance diabetic fracture healing. Human MSCs were locally introduced to femur fractures in streptozotocin-induced diabetic mice, and the quality of de novo bone was assessed eight weeks later. Biodistribution analysis demonstrated that the cells remained in situ for three days following administration. Bone bridging was evident in all animals. However, a large reparative callus was retained, indicating non-union. µCT analysis elucidated comparable callus dimensions, bone mineral density, bone volume/total volume, and volume of mature bone in all groups that received cells as compared to the saline-treated controls. Four-point bending evaluation of flexural strength, flexural modulus, and total energy to re-fracture did not indicate a statistically significant change as a result of cellular administration. An ex vivo lymphocytic proliferation recall assay indicated that the xenogeneic administration of human cells did not result in an immune response by the murine recipient. Due to this dataset, the administration of non-diabetic bone marrow-derived MSCs did not support fracture healing in this pilot study.

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Saxagliptin affects long-bone microarchitecture and decreases the osteogenic potential of bone marrow stromal cells

European Journal of Pharmacology ◽

10.1016/j.ejphar.2014.01.028 ◽

2014 ◽

Vol 727 ◽

pp. 8-14 ◽

Cited By ~ 16

Author(s):

María Laura Sbaraglini ◽

María Silvina Molinuevo ◽

Claudia Sedlinsky ◽

León Schurman ◽

Antonio Desmond McCarthy

Keyword(s):

Bone Marrow ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Bone Microarchitecture ◽

Marrow Stromal Cells ◽

Long Bone ◽

Osteogenic Potential

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Clinical Application of Bone Marrow Mesenchymal Stem/Stromal Cells to Repair Skeletal Tissue

International Journal of Molecular Sciences ◽

10.3390/ijms21249759 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9759

Author(s):

Agnieszka Arthur ◽

Stan Gronthos

Keyword(s):

Bone Marrow ◽

Stromal Cells ◽

Genetic Manipulation ◽

Bioactive Molecules ◽

Long Bone ◽

Differentiation Potential ◽

Skeletal Tissue ◽

Recent Developments ◽

Multipotent Differentiation ◽

Craniofacial Defects

There has been an escalation in reports over the last decade examining the efficacy of bone marrow derived mesenchymal stem/stromal cells (BMSC) in bone tissue engineering and regenerative medicine-based applications. The multipotent differentiation potential, myelosupportive capacity, anti-inflammatory and immune-modulatory properties of BMSC underpins their versatile nature as therapeutic agents. This review addresses the current limitations and challenges of exogenous autologous and allogeneic BMSC based regenerative skeletal therapies in combination with bioactive molecules, cellular derivatives, genetic manipulation, biocompatible hydrogels, solid and composite scaffolds. The review highlights the current approaches and recent developments in utilizing endogenous BMSC activation or exogenous BMSC for the repair of long bone and vertebrae fractures due to osteoporosis or trauma. Current advances employing BMSC based therapies for bone regeneration of craniofacial defects is also discussed. Moreover, this review discusses the latest developments utilizing BMSC therapies in the preclinical and clinical settings, including the treatment of bone related diseases such as Osteogenesis Imperfecta.

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Does osteogenic potential of clonal human bone marrow mesenchymal stem/stromal cells correlate with their vascular supportive ability?

Stem Cell Research & Therapy ◽

10.1186/s13287-018-1095-7 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Alison T. Merryweather-Clarke ◽

David Cook ◽

Barbara Joo Lara ◽

Peng Hua ◽

Emmanouela Repapi ◽

...

Keyword(s):

Bone Marrow ◽

Stromal Cells ◽

Human Bone ◽

Human Bone Marrow ◽

Osteogenic Potential

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Incidence, Costs and Predictors of Non-Union, Delayed Union and Mal-Union Following Long Bone Fracture

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph15122845 ◽

2018 ◽

Vol 15 (12) ◽

pp. 2845 ◽

Cited By ~ 17

Author(s):

Christina Ekegren ◽

Elton Edwards ◽

Richard de Steiger ◽

Belinda Gabbe

Keyword(s):

Fracture Healing ◽

Hospital Admissions ◽

Femoral Shaft ◽

Hospital Length Of Stay ◽

Long Bone ◽

Future Research ◽

Related Factors ◽

Femoral Shaft Fractures ◽

Non Union ◽

Shaft Fractures

Fracture healing complications are common and result in significant healthcare burden. The aim of this study was to determine the rate, costs and predictors of two-year readmission for surgical management of healing complications (delayed, mal, non-union) following fracture of the humerus, tibia or femur. Humeral, tibial and femoral (excluding proximal) fractures registered by the Victorian Orthopaedic Trauma Outcomes Registry over five years (n = 3962) were linked with population-level hospital admissions data to identify two-year readmissions for delayed, mal or non-union. Study outcomes included hospital length-of-stay (LOS) and inpatient costs. Multivariable logistic regression was used to determine demographic and injury-related factors associated with admission for fracture healing complications. Of the 3886 patients linked, 8.1% were readmitted for healing complications within two years post-fracture, with non-union the most common complication and higher rates for femoral and tibial shaft fractures. Admissions for fracture healing complications incurred total costs of $4.9 million AUD, with a median LOS of two days. After adjusting for confounders, patients had higher odds of developing complications if they were older, receiving compensation or had tibial or femoral shaft fractures. Patients who are older, with tibial and femoral shaft fractures should be targeted for future research aimed at preventing complications.

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Predictors of fracture healing in patients with recalcitrant nonunions treated with autologous culture expanded bone marrow‐derived mesenchymal stromal cells

Journal of Orthopaedic Research® ◽

10.1002/jor.24184 ◽

2019 ◽

Vol 37 (6) ◽

pp. 1303-1309 ◽

Cited By ~ 4

Author(s):

Atanu Bhattacharjee ◽

Jan H. Kuiper ◽

Sally Roberts ◽

Paul E. Harrison ◽

Victor N. Cassar‐Pullicino ◽

...

Keyword(s):

Bone Marrow ◽

Fracture Healing ◽

Mesenchymal Stromal Cells ◽

Stromal Cells

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Isolation Yield and Osteogenic Potential of Human Bone Marrow Stromal Cells are Maintained Irrespective of Age or Gender

Key Engineering Materials ◽

10.4028/www.scientific.net/kem.361-363.1149 ◽

2007 ◽

Vol 361-363 ◽

pp. 1149-1152

Author(s):

Jeong Joon Yoo ◽

Jeon Hyun Bang ◽

Kyung Hoi Koo ◽

Kang Sup Yoon ◽

Hee Joong Kim

Keyword(s):

Bone Marrow ◽

Osteogenic Differentiation ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Mononuclear Cells ◽

Marrow Stromal Cells ◽

Human Bone ◽

Human Bone Marrow ◽

Osteogenic Potential ◽

Donor Age

The relationships between donor age and gender and initial isolation yield and the osteogenic potentials of human bone marrow stromal cells (hBMSCs) have not been clearly elucidated. The authors investigated whether isolation yields and the osteogenic differentiation potentials of hBMSCs are indeed dependent on donor age or gender. Fresh bone marrow was aspirated from iliac crest of 72 donors (mean age 54.1 years; range, 23-84 years; 39 men and 33 women) undergoing total hip arthroplasty. Numbers of mononuclear cells, numbers of colony forming unit-fibroblasts (CFU-Fs) and alkaline phosphatase (ALP)-positive CFU-Fs, and numbers of BMSCs after isolation culture were not found to be significantly dependent on donor age or gender. Moreover, no significant age- or gender-related differences were observed in terms of the proliferation activities, ALP activities, and calcium contents of BMSCs during in vitro osteogenic differentiation. The data obtained from 72 human donors revealed no significant age- or genderrelated differences among hBMSCs in terms of isolation yields, proliferation activities, and osteogenic potentials.

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Alendronate Can Improve Bone Alterations in Experimental Diabetes by Preventing Antiosteogenic, Antichondrogenic, and Proadipocytic Effects of AGEs on Bone Marrow Progenitor Cells

BioMed Research International ◽

10.1155/2016/5891925 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Sara Rocío Chuguransky ◽

Ana María Cortizo ◽

Antonio Desmond McCarthy

Keyword(s):

Bone Marrow ◽

Experimental Diabetes ◽

Bone Microarchitecture ◽

Bone Matrix ◽

Diabetic Rats ◽

Long Bone ◽

Osteogenic Potential ◽

Bone Marrow Progenitor

Bisphosphonates such as alendronate are antiosteoporotic drugs that inhibit the activity of bone-resorbing osteoclasts and secondarily promote osteoblastic function. Diabetes increases bone-matrix-associated advanced glycation end products (AGEs) that impair bone marrow progenitor cell (BMPC) osteogenic potential and decrease bone quality. Here we investigated the in vitro effect of alendronate and/or AGEs on the osteoblastogenic, adipogenic, and chondrogenic potential of BMPC isolated from nondiabetic untreated rats. We also evaluated the in vivo effect of alendronate (administered orally to rats with insulin-deficient Diabetes) on long-bone microarchitecture and BMPC multilineage potential. In vitro, the osteogenesis (Runx2, alkaline phosphatase, type 1 collagen, and mineralization) and chondrogenesis (glycosaminoglycan production) of BMPC were both decreased by AGEs, while coincubation with alendronate prevented these effects. The adipogenesis of BMPC (PPARγ, intracellular triglycerides, and lipase) was increased by AGEs, and this was prevented by coincubation with alendronate. In vivo, experimental Diabetes (a) decreased femoral trabecular bone area, osteocyte density, and osteoclastic TRAP activity; (b) increased bone marrow adiposity; and (c) deregulated BMPC phenotypic potential (increasing adipogenesis and decreasing osteogenesis and chondrogenesis). Orally administered alendronate prevented all these Diabetes-induced effects on bone. Thus, alendronate could improve bone alterations in diabetic rats by preventing the antiosteogenic, antichondrogenic, and proadipocytic effects of AGEs on BMPC.

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