Anna Spagnoli

Regenerative effects of transplanted mesenchymal stem cells in fracture healing.

Mesenchymal stem cells (MSC) have a therapeutic potential in patients with fractures to reduce the time of healing and treat nonunions. The use of MSC to treat fractures is attractive for several reasons. First, MSCs would be implementing conventional reparative process that seems to be defective or protracted. Secondly, the effects of MSCs treatment would be needed only for relatively brief duration of reparation. However, an integrated approach to define the multiple regenerative contributions of MSC to the fracture repair process is necessary before clinical trials are initiated. In this study, using a stabilized tibia fracture mouse model, we determined the dynamic migration of transplanted MSC to the fracture site, their contributions to the repair process initiation, and their role in modulating the injury‐related inflammatory responses. Using MSC expressing luciferase, we determined by bioluminescence imaging that the MSC migration at the fracture site is time‐ and dose‐dependent and, it is exclusively CXCR4‐dependent. MSC improved the fracture healing affecting the callus biomechanical properties and such improvement correlated with an increase in cartilage and bone content, and changes in callus morphology as determined by micro‐computed tomography and histological studies. Transplanting CMV‐Cre‐R26R‐Lac Z‐MSC, we found that MSCs engrafted within the callus endosteal niche. Using MSCs from BMP‐2‐Lac Z mice genetically modified using a bacterial artificial chromosome system to be β‐gal reporters for bone morphogenic protein 2 (BMP‐2) expression, we found that MSCs contributed to the callus initiation by expressing BMP‐2. The knowledge of the multiple MSC regenerative abilities in fracture healing will allow design of novel MSC‐based therapies to treat fractures. STEM CELLS 2009;27:1887–1898

Role of mesenchymal stem cells in regenerative medicine: application to bone and cartilage repair

Background: Mesenchymal stem cells (MSC) are multipotent cells with the ability to differentiate into mesenchyme-derived cells including osteoblasts and chondrocytes. Objective: To provide an overview and expert opinion on the in vivo ability of MSC to home into tissues, their regenerative properties and potential applications for cell-based therapies to treat bone and cartilage disorders. Methods: Data sources including the PubMed database, abstract booklets and conference proceedings were searched for publications pertinent to MSC and their properties with emphasis on the in vivo studies and clinical use in cartilage and bone regeneration and repair. The search included the most current information possible. Conclusion: MSC can migrate to injured tissues and some of their reparative properties are mediated by paracrine mechanisms including their immunomodulatory actions. MSC possess a critical potential in regenerative medicine for the treatment of skeletal diseases, such as osteoarthritis or fracture healing failure, where treatments are partially effective or palliative.

Vascular endothelial growth factor (VEGF) in children, adolescents and young adults with Type 1 diabetes mellitus: relation to glycaemic control and microvascular complications.

SUMMARY

Mesenchymal stem cells at the intersection of cell and gene therapy

Importance of the field : Mesenchymal stem cells have the ability to differentiate into osteoblasts, chondrocytes and adipocytes. Along with differentiation, MSCs can modulate inflammation, home to damaged tissues and secrete bioactive molecules. These properties can be enhanced through genetic-modification that would combine the best of both cell and gene therapy fields to treat monogenic and multigenic diseases. Areas covered in this review: Findings demonstrating the immunomodulation, homing and paracrine activities of MSCs followed by a summary of the current research utilizing MSCs as a vector for gene therapy, focusing on skeletal disorders, but also cardiovascular disease, ischemic damage and cancer. What the reader will gain: MSCs are a possible therapy for many diseases, especially those related to the musculoskeletal system, as a standalone treatment, or in combination with factors that enhance the abilities of these cells to migrate, survive or promote healing through anti-inflammatory and immunomodulatory effects, differentiation, angiogenesis or delivery of cytolytic or anabolic agents. Take home message: Genetically-modified MSCs are a promising area of research that would be improved by focusing on the biology of MSCs that could lead to identification of the natural and engrafting MSC-niche and a consensus on how to isolate and expand MSCs for therapeutic purposes.

Mesenchymal Stem Cells Expressing Insulin‐like Growth Factor‐I (MSCIGF) Promote Fracture Healing and Restore New Bone Formation in Irs1 Knockout Mice: Analyses of MSCIGF Autocrine and Paracrine Regenerative Effects

Failures of fracture repair (nonunions) occur in 10% of all fractures. The use of mesenchymal stem cells (MSC) in tissue regeneration appears to be rationale, safe, and feasible. The contributions of MSC to the reparative process can occur through autocrine and paracrine effects. The primary objective of this study is to find a novel mean, by transplanting primary cultures of bone marrow‐derived MSCs expressing insulin‐like growth factor‐I (MSCIGF), to promote these seed‐and‐soil actions of MSC to fully implement their regenerative abilities in fracture repair and nonunions. MSCIGF or traceable MSCIGF‐Lac‐Z were transplanted into wild‐type or insulin‐receptor‐substrate knockout (Irs1−/−) mice with a stabilized tibia fracture. Healing was assessed using biomechanical testing, microcomputed tomography (μCT), and histological analyses. We found that systemically transplanted MSCIGF through autocrine and paracrine actions improved the fracture mechanical strength and increased new bone content while accelerating mineralization. We determined that IGF‐I adapted the response of transplanted MSCIGF to promote their differentiation into osteoblasts. In vitro and in vivo studies showed that IGF‐I‐induced osteoglastogenesis in MSCs was dependent of an intact IRS1‐PI3K signaling. Furthermore, using Irs1−/− mice as a nonunion fracture model through altered IGF signaling, we demonstrated that the autocrine effect of IGF‐I on MSC restored the fracture new bone formation and promoted the occurrence of a well‐organized callus that bridged the gap. A callus that was basically absent in Irs1−/− left untransplanted or transplanted with MSCs. We provided evidence of effects and mechanisms for transplanted MSCIGF in fracture repair and potentially to treat nonunions. STEM CELLS 2011;29:1537–1548

Cartilage disorders: potential therapeutic use of mesenchymal stem cells.

Chondrogenesis is a well-orchestrated process driven by chondroprogenitors that undergo to condensation, proliferation and chondrocyte differentiation. Because cartilage lacks regenerative ability, treatments for cartilage diseases are primarily palliative. Adult bone marrow contains a reservoir of mesenchymal stem cells (MSC) with in vitro and in vivo potential of becoming cartilage. To optimize the potential therapeutic use of MSC in cartilage disorders, we need to understand the mechanisms by which growth factors determine their chondrogenic potential. Insulin-like growth factors (IGFs) play a central role in chondrogenesis as indicated by the severe growth failure observed in animals carrying null mutations of Igfs and Igf1R genes. We have found that IGF-I has potent chondrogenic effects in MSC. Effects are similar to transforming growth factor-Beta (TGF-Beta). Insulin-like growth factor binding protein-3 (IGFBP-3), well characterized as IGF carrier, has intrinsic bioactivities that are independent of IGF binding. IGFBP-3 levels are increased in degenerative cartilage diseases such as osteoarthritis. We have demonstrated that IGFBP-3 has IGF-independent growth inhibitory effects in chondroprogenitors. We now show that IGFBP-3 induces MSC apoptosis and antagonizes TGF-Beta chondroinductive effects in chondroprogenitors. Understanding IGF-I chondroinductive and IGFBP-3 chondroinhibitory effects would provide critical information to optimize the therapeutic use of MSC in cartilage disorders.

Detection of HCV RNA in gastric mucosa-associated lymphoid tissue by in situ hybridization: Evidence of a new extrahepatic localization of HCV with increased risk of gastric malt lymphoma

Detection of HCV RNA in gastric mucosa—associated lymphoid tissue by in situ hybridization: evidence of a new extrahepatic localization of HCV with increased risk of gastric malt lymphoma

Serum angiogenin concentrations in young patients with diabetes mellitus

Background  Angiogenin serum levels were measured in a large group of type 1 diabetic young patients, looking at whether increased Angiogenin concentrations are associated with long‐term glycemic control and microvascular complications.

Evaluation of the components of insulin-like growth factor (IGF)-IGF binding protein (IGFBP) system in adolescents with type 1 diabetes and persistent microalbuminuria: relationship with increased urinary excretion of IGFBP-3 18 kD N-terminal fragment.

IGFs and their binding proteins (IGFBPs) have an important role in controlling glucose homeostasis and there is evidence to support their involvement in complications related to type I diabetes. The aim of this study was to evaluate the components of the IGF‐IGFBP system in adolescents with type 1 diabetes that had developed persistent microalbuminuria (MA).

Increased circulating IL-8 is associated with reduced IGF-1 and related to poor metabolic control in adolescents with type 1 diabetes mellitus

BACKGROUND A dysregulated growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis is well-recognized in children and adolescents with type 1 diabetes mellitus (T1DM). Decreased IGF-1 levels can also be found in chronic inflammatory diseases, while hyperglycemia promotes inflammatory cytokine production. Therefore, inflammatory cytokines may link poor metabolic control with GH/IGF-1 axis changes. This study examined the relationship between serum inflammatory cytokines and IGF-1 in adolescents (age 13-18) with TIDM in chronic poor (n=17) or favorable (n=19) glucose control. Poor control (PC) was defined as >or=3, consistent HbA1C>9% during the previous 2 years, while favorable control (FC) was consistent levels of HbA1C<9%. RESULTS HbA1C (FC: 7.5+/-0.6%; PC: 10.5+/-0.9%, p<0.001) and interleukin (IL)-8 (FC: 3.7+/-4.0 pg/ml; PC: 7.4+/-4.3 pg/ml, p=0.01) were increased and IGF-1 (FC: 536.5+/-164.3 ng/ml; PC: 408.9+/-157.1 ng/ml, p=0.03) was decreased in patients with poor control compared to patients with favorable control. Moreover, IL-8 was inversely correlated with IGF-1 (r=-0.40, p=0.03) and positively correlated with HbA1C (r=0.36, p=0.03). CONCLUSIONS In adolescents with T1DM and chronic, poor glucose control, increased serum IL-8 is associated with reduced IGF-1 suggesting a pro-inflammatory milieu that may contribute to alterations in the GH/IGF-1 axis.