Narrow Results

Priming X-irradiation with 0.3-0.5 Gy induces radio-resistance in C57BL/6 strain of mice 2 weeks afterward. Elements in the bone marrow, sampled 11 days after challenging exposure to 5.0 Gy, were determined by PIXE. The challenging irradiation decreased Mg, P, S, K, Ca and Zn as well as dried bone marrow weight. The pre-irradiation enhanced recovery of these levels, indicating stimulated recovery of the metabolism in the tissue. Fe in both control (without pre-irradiation) and experimental groups increased to about twice the original value, showing elevated hemoglobin synthesis after challenging exposure. In previous studies we have reported that recovery of peripheral blood cell counts after sub-lethal irradiation was enhanced by the pre-irradiation. Further, study on accumulation of p53 and Bax proteins, which lead to apoptotic cell death, revealed that the pre-irradiation significantly suppressed accumulation of these proteins in the spleen after challenging irradiation with 3 Gy. These results and our present study suggest that the pre-irradiation decreased the spleen cell death, and favored re-growth of the spleen cells, resulting in stimulated recovery of metabolism for hematopoiesis in the bone marrow as well as in the spleen after challenging high dose irradiation. Stimulated recovery of Mg, P, S, K, Ca and Zn levels might indicate the importance of these elements in hematopoiesis.

Pre-irradiation with 0.3-0.5 Gy of X-rays induces radioresistance (decreased bone marrow death) in ICR and C57BL strains of mice 2 weeks afterward. Recovery of blood cell counts of thrombocytes, leukocytes and erythrocytes was enhanced by the pre-irradiation. And the radio-resistance is acquired even in splenectomized C57BL mice. Elements in the bone marrow 11 days after the challenging dose of 5.0 Gy was determined by a PIXE analysis in three groups of mice: intact (with no irradiations), without pre-irradiation (control) and pre-irradiation (experimental) groups. Challenging irradiation decreased Mg, P, S, K, Ca and Zn levels, and the pre-irradiation enhanced the recovery of those levels, i.e. stimulated metabolism in bone marrow of irradiated mice. Increase in Fe in both control and experimental groups would indicate stimulated hemoglobin synthesis after challenging irradiation.

Cells of the hematopoietic system are uniquely radiosensitive due to their rapid proliferation. Consequently, immune suppression readily and undesirably results from irradiation. Our previous studies demonstrated that geraniin isolated from Nymphaea tetragona var. angusta (water lily) had a protective effect on the splenocytes and intestinal tract of irradiated mice. This study was designed to assess the effectiveness of geraniin, an ellagitannin isolated from the water lily, in decreasing gamma ray irradiation-induced destruction of the hematopoietic system in mice. Geraniin treatment improved the survival time of bone marrow cells and maintained bone marrow integrity and also up-regulated the expression of stem cell receptors and the extent of cell mitosis. Geraniin also enhanced the proliferation and differentiation of immune cells that had been suppressed by irradiation. These results suggest geraniin is a promising agent for reconstituting hematopoietic cells after exposure to irradiation.

Baicalin is the main active ingredient primary isolated from the Chinese herb, Scutellaria baicalensis Georgi. Although baicalin can induce M2 macrophage polarization, we still do not know the subtype of macrophages polarized by baicalin. In this study, we characterized that murine bone marrow derived macrophages induced by M-CSF can be further polarized into M2_C phenotype by baicalin. The signatures of M2_C macrophages for mRNA expression like interferon regulatory factor 4 (IRF4), interleukin-10 (IL-10), MERTK and PTX3 were up-regulated. Moreover, we observed the concomitantly decreasing of tumor necrosis factor alpha (TNF-$\alpha$), interferon regulatory factor 5 (IRF5), IL-6. In contrast, M2 macrophages polarized by IL-4 increased gene transcript of arginase-1 (Arg-1) and surface marker of CD206 indicates that their identity as M2_A rather than M2_C subtypes. Interestingly, the phagocytosis as well as efferocytosis activity were significantly enhanced in M2_C macrophage polarized by baicalin and these capacities were associated with the expression of MERTK receptor. Finally, we conclude that baicalin induced M2_C macrophages polarization with both elevations of efferocytosis and anti-inflammatory activity.

Purpose: Bone morphogenetic proteins (BMPs) strongly induce osteogenesis. However, BMPs also directly or indirectly stimulate catabolic osteoclast activity, leading to strong bone resorption, especially in the bone marrow. The aim of this study was to investigate whether the combination of a local recombinant human BMP-2 (rh-BMP-2)/beta-tricalcium phosphate ($\beta$-TCP) composite with systemically administrated bisphosphonate, zoledronate (ZOL) could promote osteogenesis in a rabbit model. Methods:$\beta$-TCP columns, with or without rh-BMP-2 (30 $\mu$g/column), were implanted into the left femur canal of 20 rabbits. The animals were injected with 0.4mg of ZOL or saline 1 week after implantation. The implants were evaluated by micro-computed tomography ($\mu$-CT) and histology 6 weeks after implantation. Results:$\mu$-CT data revealed that the bone volume/tissue volume ratio of bone nodules inside $\beta$-TCP columns in combination with rh-BMP-2 and ZOL was significantly higher than that of $\beta$-TCP columns treated with rh-BMP-2, ZOL, or neither. Histological evaluation also revealed that significantly more new bone formed inside $\beta$-TCP columns treated with rh-BMP-2 and ZOL than inside $\beta$-TCP columns treated with rh-BMP-2, ZOL, or neither. Conclusion: This combination therapy contributed to the maintenance of the newly formed BMP-2-induced bone structure in the bone marrow.

This study was carried out to assess the effect of bone marrow transplant into the 47 ununited fracture sites of the long bones of the extremities in 46 patients on bone healing. Among 46 cases, there were 43 pure fractures; a case of simultaneous ipsilateral femoral and tibial osteotomies for leg lengthening; a case of ununited repositioned cryo-treated proximal half of tibia as a limb salvage; and a case of internal transport of proximal tibia.

Among the 43 pure fractures, there were 11 hypertrophic, 30 oligotrophic, and 2 gap nonunions. Bone marrow transplant was performed for any type of the delayed union and nonunion, and was also indicated in the distraction callotasis site of poor osteogenesis.

Overall union rate in 43 fractures was 55.8% (24 cases). In two gap nonunions, no callus was formed. Union was obtained in all the 11 hypertrophic nonunions and 13 (46.4%) of the 30 oligotrophic nonunions. The oligotrophic and gap nonunions responded poorly to the marrow transplant. One of the two tibial osteotomy gaps healed with good evidence of endosteal callus formation. In a femoral osteotomy site for lengthening and in an ununited repositioned site of the cryo-treated tibia, there were no visible callus at all. The average time for clinical and radiological unions in the fracture cases were 5 and 7 months on average. In our series, there were no complications, including infection.

The results in this series suggest that bone marrow transplant is a good source of callus formation or stimulant in treating the delayed union and hyper- and oligotrophic nonunions of any origin, and also enhances the callus formation at the gap of the early stage of the internal transport.

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Body, Heal Thyself?

Background: Numerous studies have indicated the presence of mesenchymal stem cells (MSCs) in the bone marrow aspirated from the vertebral body, distal femur, proximal tibia, humeral head, sternum, and iliac crest. However, their presence has not been reported in the radius thus far. In this study, we aimed to compare the number of MSCs in bone marrow aspirated from radius and iliac crest in patients with Kienböck’s disease. Furthermore, we examined the association between the number of MSCs in the bone marrow and patient age.

Methods: A total of 17 patients were recruited. Owing to difficulties in obtaining samples for 5 cases, only 12 cases were included. Hematological analyses and fibroblastic colony-forming unit (CFU-F) assay were performed using bone marrow samples aspirated from the radius (group R), the first sample aspirated from the iliac crest (group I-1), and the second sample aspirated from the iliac crest (group I-2). The CFU-F numbers among the three groups were compared using Mann–Whitney U-test. Pearson’s correlation coefficient was calculated to evaluate the association between the CFU-F numbers and patient age.

Results: The average numbers of CFU-Fs/ml in the bone marrow samples from the R, I-1, and I-2 groups were 3.4, 57.3, and 13.7, respectively. The CFU-F number in Group I-1 was significantly higher than that in the other two groups; the CFU-F number was lower in group R than in group I-2. The correlation coefficients were -0.168, 0.166, and 0.036 for samples from groups R, I-1, and I-2, respectively. No significant association between the CFU-F numbers and patient age was observed.

Conclusions: The presence of MSCs in the radius was indicated by CFU-Fs in patients with Kienböck’s disease. The number of CFU-Fs was lower in the radius than in the iliac crest; the CFU-F number was not associated with patient age.

The skeletal system of adult mammals fulfills many roles including providing structural support for the body musculature and functioning as a storehouse for calcium. Additionally, it also serves as a repository for the bone marrow, which represents a rich source of stem cells. The hematopoietic stem cell (HSC), which generates all lineages of the immune system and blood, was the first stem cell shown to reside within adult bone marrow and remains the best characterized with respect to phenotype and function. Soon after the discovery of the HSC a separate cell population in marrow was described with the capacity to form ectopic bone tissue in vivo. This stem cell population, referred to as mesenchymal stem cells or multipotent marrow stromal cells (MSCs) has since been shown to differentiate into various connective tissue cell types including adipocytes, chondrocytes, myoblasts, and osteoblasts. Most recently, adult bone marrow has also been shown to harbor endothelial progenitor cells (EPCs) that participate in postnatal vasculogenesis. Therefore, bone marrow appears unique with respect to the fact that it harbors three physically and functionally distinct adult stem cell populations. Herein I review the discovery of these stem cells and emphasize their characterization and function. Moreover, I describe recent findings that indicate these stem cells are derived from a common precursor during embryonic development. This fact may account for their phenotypic similarities and functional interdependency.

The observations that mice exposed to otherwise lethal irradiation could survive if their spleens or marrows were shielded, or if they received an infusion of bone marrow, led to the first attemps of bone marrow transplantation in humans in the mid-1950s by E. D. Thomas and J. Ferrebee. Thanks to Thomas' persistence despite criticism and initial clinical failures, and thanks to the development of a canine model of bone marrow transplantation by Thomas and Storb, the role of allogeneic hematopoietic cell transplantation (HCT) changed during the last 50 years from a desperate therapeutic maneouver plagued by apparently insurmountable complications to a curative treatment modality for thousands of patients with hematologic diseases. Further, it was recognized that allogeneic immunocompetent cells contained in the graft mediated therapeutic antitumor effects independent of the action of the high-dose therapy. These were termed graft-versus-tumor (GVT) effects. This prompted the recent development of non-myeloablative conditioning regimens for allogeneic HCT that have allowed offering this treatment modality in elderly patients and those with comorbid conditions. While hematopoietic stem cells were identified in the early 1960s, identification of other types of stem cells such as mesenchymal stem cells or embryonic stem cells might pave the way for stem cell therapy in regenerative medicine in the future.

In spite of the current notable advances in surgical management of critical limb ischemia (CLI), the most severe form of peripheral artery disease, it is still associated with the high frequency of amputations, lethality and low quality of life. Although the compensatory opportunities are mainly exhausted in the treatment of CLI, an efficient medical intervention remains possible. The purpose of this intervention is to eliminate a pronounced imbalance between the blood supply of the ischemic tissues and their metabolic needs. The physiological compensatory arteriogenesis, which actively proceeds at the initial stages of limb ischemia, almost ceases to the beginning of its transition into the final stages. Therefore, research efforts are focused on those technologies for tissue repair which are directed at the activation and expansion of the microvascular bed (angiogenesis) in the affected limb. Cell therapy, having been actively studied from the beginning of 2000s, is one of such approaches. This review discusses in-depth the advantages of different cell types for the CLI therapy, including peripheral bone marrow-derived mononuclear cells (BMMNCs) and mesenchymal stem cells (BMMSCs). The results of the most important pre-clinical and clinical studies, including the ongoing clinical trials, involving cell-based approach for CLI therapy have also been discussed besides optimization of the cell delivery techniques with or without the use of biomaterials as cell carriers.

Mesenchymal stem cells (MSCs) are adult sourced stem cells which are currently the popular choice of therapeutics in regenerative medicine. They can be extracted from various adult tissues and expanded in laboratories for infusions. In the Indian scenario, regenerative medicine-based therapies developed around MSCs surfaced drastically during the COVID-19 pandemic wherein different sources of MSCs were explored in the treatment of this deadly disease with demonstrated positive results. These tissue-specific MSCs are similar in their functions; however, they exhibit elusive differences that distinguish them based on their mode of action and inherent therapeutic abilities which need to be researched in detail for their optimal clinical applications. This chapter explores these tissue-specific differences among the varied sources of MSCs and the current scenario of stem cell therapy.

Preterm birth results in several respiratory complications, one of the major causes of infant morbidity and mortality. There is a high risk of development of chronic lung disease and respiratory distress syndrome among preterm infants. In addition, follow-up studies show that the functional impairment of airways is commonly seen in preterm children. Bronchopulmonary dysplasia (BPD) is one form of chronic lung disease affecting most premature newborns and infants, and results from lung damages. Studies on surviving children with BPD suggest persisting defects in the structure of both the airways and the parenchyma of the lung. Preterm birth survivors have several respiratory consequences such as immediate breathing challenges due to lungs that are still underdeveloped, which usually manifest as respiratory distress syndrome (RDS). The current therapies for neonatal lung diseases enable the survival of preterm infants who are born at week 22 of pregnancy or later, although they still suffer from some health consequences. Stem cells have therapeutic applications and potential for the treatment of infants with pulmonary complications associated with preterm birth, such as BPD.