Mobilization of Stem Cells from the Bone Marrow Is Required for Neovascularization of Ischemic Limbs in Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4233-4233
Author(s):  
Jeong-A Kim ◽  
Chang -Hoon Lee ◽  
Jin-A. Yoon ◽  
Woo-Sung Min ◽  
Chun-Choo Kim
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hind Limb ◽  
Limb Ischemia ◽  
Hind Limb Ischemia ◽  
Ischemic Limb ◽  
Group 3 ◽  
Group 2 ◽  
Surgically Induced ◽  
Group 1

Abstract We examined whether the injection of bone marrow mononuclear cells (BM-MNCs) or mesenchymal stem cells (MSCs) might augment angiogenesis and collateral vessel formation in a mouse model of hind limb ischemia. C57BL/6 BM-MNCs were isolated by centrifugation through a Histopaque density gradient and MSCs were obtained from C57BL/6 bone marrow and cultured in low-glucose DMEM media. Unilateral hind limb ischemia was surgically induced in C57BL/6 mice (control; n=4), and autologous BM-MNCs (Group 1; n=4, 1.8±0.2 x107/animal) or MSCs (Group 2; n=4, 1.0±0.14 x106/animal) or BM-MNCs and MSCs (Group 3; n=4, 2.3±0.1 x107 and 1.1±0.21 x106/animal) were transplanted into the ischemic tissue. Six weeks after transplantation, the group 1, group 2 and group 3 had a higher capillary/muscle ratio (0.82±0.12 vs 0.85±0.08 vs 0.97 ±0.03) than control (0.46±0.12, p<0.05) (Fig. 1). This result suggested that direct local transplantation of autologous BM-MNCs or MSCs seems to be a useful strategy for therapeutic neovascularization in ischemic tissues. Next, we evaluated whether bone marrow derived stem cells were participated in the process of local injected stem cells forming new vessels. In general, mobilizing stem cells from bone marrow to local site, MMP-9 has been known as an important molecule. So we used the MMP-9 deficient KO mice and wild type, 129SvEv mice were used in the experiments. Autologous BM-MNCs and MSCs were transplanted into the ischemic limb in MMP-9 (−/−) (n=4) after unilateral hind limb ischemia was surgically induced and then the same experiments was done in MMP-9 (+/+) mice (n=4). The number of the injected BM-MNCs and MSCs was 2.2±0.05 x107 and 0.87±0.17 x106/animal in MMP-9 (−/−). And the number of the injected BM-MNCs and MSCs was 2.1±0.17 x107 and 0.98±0.09 x106/animal in MMP-9 (+/+). No difference was seen in the BM-MNCs and MSCs were injected or not (0.52±0.07 vs 0.49±0.03,) in MMP-9 (−/−). But, in the case that BM-MNCs and MSCs were injected, the higher capillary/muscle ratio was seen in MMP-9 (+/+) compared to control (0.86 ±0.09 vs 0.49±0.03, P<0.05) (Fig 2). This data indicated that the mobilization of bone marrow derived stem cells would have an important role in the neovasculrization although the stem cells were injected directly into the muscle of ischemic limb. Figure Figure Figure Figure

Leukemic and Hematopoietic Stem Cells Compete for the Same Functional Marrow Niche in a MLL-AF9 Murine Leukemia Model

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4897-4897
Author(s):  
Ronan G. Desmond ◽  
Taha Bat ◽  
Olena Kamenyeva ◽  
Benjamin Mizukawa ◽  
James C. Mulloy ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Murine Model ◽  
Leukemic Cells ◽  
Hematopoietic Stem ◽  
Group 4 ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Abstract 4897 Much is known regarding the location, cellular composition, signaling pathways, and functional role of the normal hematopoietic stem cell (HSC) niche in the bone marrow microenvironment. Microenvironmental cells including osteoblasts, other specialized mesenchymal cells, and vascular endothelial cells exert control over HSC self-renewal, differentiation, and engraftment. Niche occupancy appears to be competitive and limiting in terms of controlling the number of HSCs per organism. Leukemia stem cells (LSCs), through their inherent properties of quiescence and resistance to chemotherapeutic agents, are thought to be one of the principal mechanisms underlying disease relapse in patients. Much less is known regarding the interaction of LSCs and the marrow microenvironment. It is not clear whether LSCs localize to the same niches as HSCs, compete with HSCs for niche occupancy, or share dependence on niche signals, and whether those signals affect tumor responses to chemotherapy. Using a human pre-B ALL xenograft mouse model, Colmone et al (Science 2008) recently showed that leukemic cells may alter the normal microenvironment, resulting in initial homing of transplanted normal HSPCs in distinct atypical niches. Shiozawa et al (JCI 2011) showed that metastatic prostate cancer cells, a tumor type known to target bone, impeded HSC engraftment in a murine model, suggesting competition for the same niche. To investigate the relationship between HSC and LSC niche localization and functional occupancy, we used murine progenitor cells transduced with an MLL-AF9 vector expressing GFP in a murine syngeneic competitive transplantation model. MLL-AF9 cells are highly enriched for LSCs, particularly the c-kit+ compartment (Somervaille Cancer Cell 2006). We found that between approximately 21% and 24% of cells were c-kit+ by FACS in 2 separate experiments. In our model, mice transplanted with unsorted MLL-AF9 cells (1×107) died of AML with a latency of 11–14 days. We cotransplanted a fixed number of MLL-AF9-GFP cells (1×106) with increasing numbers of normal mouse whole bone marrow (WBM) cells, derived from dsRed transgenic mice to facilitate distinction from the GFP+ MLL-AF9 cells, into mice irradiated with 1000 rads: 1×105 [group 1], 1×106 [group 2], 1×107 [group 3], 5×107 [group 4]. Control groups received 1×105 and 1×106 normal WBM cells only. Survival was monitored daily. The control group receiving 1×105 cells only all died with median time to death of 16.5 days from lack of count recovery, those receiving 1×106 cells are still alive 35 days after transplant, indicating that 1×106 cells is adequate to rescue from irradiation. Mice were bled weekly until death and samples were analyzed by flow cytometry. Complete blood counts, blood smears, and splenic sections were obtained from these mice. As expected, there were no circulating blasts detected 7 days post transplant and all mice were healthy. However, 14 days after transplant the percentages of GFP+ leukemic cells detected in the blood were inversely proportional to the number of normal dsRed WBM cells transplanted (group 1 vs. group 2 vs. group 3 vs. group 4 mean percentage of GFP+ cells, 83.97 v 66.53 v 18.73 v 9.275 p< 0.0001). At day 15, mice from group 1, but not from groups 2 to 4, became moribund and were sacrificed. Spleens in this group were heavier than in those mice transplanted with 1×105 normal WBM cells alone and 2 out of 3 showed leucocytosis compared to leucopenia in all mice in the group transplanted with normal cells alone. When mice in the other groups had blood samples taken for analysis while moribund, GFP+ cells were greater than 80% suggesting that mice in group 1 died from complications relating to leukemic infiltration. Confocal microscopy confirmed the colocalization of normal HSPCs and MLL-AF9-GFP LSCs in the niche. Most interestingly, survival was proportional to the numbers of normal WBM cells transplanted, with a continuous delay in leukemic death proportional to the number of normal WBM cells cotransplanted with the same dose of MLL-AF9 cells (Figure 1). Hence, this murine model of leukemia suggests that normal and leukemic cells compete for the same functional niche, that manipulation of the niche could impact on response to anti-leukemic therapies, and that cell dose in the context of stem cell transplantation for leukemia may have an impact on outcome via niche competition. Figure 1 Figure 1. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The healing effect of bone marrow-derived stem cells and aquatic activity in Achilles tendon injury

2019 ◽  
Vol 70 (1) ◽  
pp. 1373
Author(s):  
H. SHEIKHANI-SHAHIN ◽  
D. MEHRABANI ◽  
M. J. ASHRAF ◽  
H. RAJABI ◽  
M. NOROUZIAN ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Achilles Tendon ◽  
Tendon Injury ◽  
Tendon Injuries ◽  
Histological Evaluation ◽  
Healing Effect ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

The common treatment recommended for Achilles tendon rupture as the most common tendon injury during exercise is surgical intervention, while it eventually causes various clinical problems. This study assessed the healing effect of bone marrow-derived stem cells (BMSCs) and aquatic activities in Achilles tendon injury. Forty rats were randomly divided into 5 equal groups. Group 1 underwent aquatic activity, 72 h after a crush lesion formed on Achilles tendon, group 2 received 1×106 intra-articular BMSCs post-tendon injury, group 3 had aquatic activity together with BMSCs transplantation after tendon damage, group 4 just experienced tendon injury without any treatment intervention and group 5 was considered as the control group while did not undergo any tendon injury and did not receive any treatment measure. After 8 weeks, the animals were sacrificed and the tendons were transferred in 10% formalin for histological evaluation. There was a significant increase in fibroblast number in group 3 in comparison to other groups. However, there was a significant increase in collagen deposition in groups 2, 3 and 5 in comparison to group 1 and 4. A significant decrease was noted for cellularity in group 2 when compared to groups 1 and 4. Regarding tendon diameter in group 3; a significant healing was observed when compared to groups 2, 4 and 5. It was shown that aquatic activity together with cell transplantation was an effective therapeutic measure enhancing the healing in tendon injuries. These findings can open a window in sport medicine in treatment of tendon injuries.

scholarly journals Feline Leukemia Virus-associated Enteritis—A Condition with Features of Feline Panleukopenia

1987 ◽  
Vol 24 (1) ◽  
pp. 1-4 ◽  
Author(s):  
M. Reinacher
Keyword(s):  
Bone Marrow ◽  
Leukemia Virus ◽  
Feline Leukemia Virus ◽  
Lymphoid Tissues ◽  
Post Mortem ◽  
The Third ◽  
Histopathological Alterations ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Infection with feline leukemia virus (FeLV) was demonstrated immunohistologically in 218 necropsied cats suffering from enteritis. The animals were divided into three groups according to histopathological criteria. The first group exhibited the signs of feline panleukopenia in intestine, lymphoid tissues, and bone marrow. Only 1.6% of these animals were FeLV-infected. The animals of the second group had histopathological alterations as seen in cats suffering from feline panleukopenia, but these were found only in the intestine and not in lymphoid tissues or bone marrow. Of these 71.9% were infected with FeLV. The third group consisted of all other cats suffering from enteritis of which 6.3% were FeLV-positive. The association between FeLV infection and the lesions seen in the animals of group 1 (feline panleukopenia) and group 3 (other types of enteritis) is statistically not significant whereas the alterations exhibited by the cats of group 2 are significantly FeLV-associated. Cats with FeLV-associated enteritis (group 2) are of a mean age of about 2.5 years and are significantly older than animals with feline panleukopenia which are of a mean age of about half a year. Thus a FeLV-associated enteritis exists as a histopathologically recognizable condition which sometimes might be mistaken for feline panleukopenia in routine post-mortem investigations.

Human Umbilical Cord-Derived Mesenchymal Stem Cells Relieve Hind Limb Ischemia by Promoting Angiogenesis in Mice

2019 ◽  
Vol 28 (20) ◽  
pp. 1384-1397 ◽  
Author(s):  
Zhecun Wang ◽  
Liang Zheng ◽  
Chong Lian ◽  
Yunling Qi ◽  
Wen Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Hind Limb ◽  
Limb Ischemia ◽  
Human Umbilical Cord ◽  
Hind Limb Ischemia

Abstract 3915: Del-1, A New β2-Integrin Ligand, Which Inhibits Adhesion and Homing of Progenitor Cells

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Emmanouil Chavakis ◽  
Andreas Hain ◽  
Alessia Orlandi ◽  
Guillaume Carmona ◽  
Thomas Quertermous ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Hind Limb ◽  
Limb Ischemia ◽  
Inflammatory Cells ◽  
Inhibitory Effect ◽  
Hind Limb Ischemia ◽  
Beta2 Integrins ◽  
Integrin Ligand

Progenitor cells (PC) are recruited to ischemic tissues and improve neovascularization. Beta2-integrins are essential for adhesion, transmigration and homing of PC to ischemic tissues. Developmental Endothelial Locus-1 (Del-1) is an extracellular matrix protein, that binds alphaVbeta3- and alphaVbeta5-integrins and is up-regulated during ischemia. Therefore, we investigated the role of endogenous Del-1 for angiogenesis and homing functions of PC. The Del-1-deficient mice (Del-1 −/− ) displayed a significantly increased angiogenic response in ischemic muscles in comparison to the wild type (WT) mice in the model of hind limb ischemia. However, when we assessed the role of Del-1 in HUVEC in vitro , silencing of Del-1 by siRNA did not affect angiogenic sprouting. Moreover, the ischemic muscles of Del-1 −/− mice displayed a higher infiltration with CD45 + hematopoietic cells than WT mice, suggesting that Del-1 may have an inhibitory effect on homing of PC and inflammatory cells to ischemic tissues. Interestingly, in adhesion assays human endothelial progenitor cells (EPC) and murine Lin − progenitor cells bound to Del-1 via beta2-integrins, but not via the alphaVbeta3- and alphaVbeta5- integrins. Furthermore, soluble Del-1 significantly inhibited the adhesion of EPC to HUVEC monolayers and to the major beta2-integrin-ligand, ICAM-1, raising the possibility that Del-1 is a beta2-integrin-inhibitor. Indeed, WT murine bone marrow mononuclear cells displayed higher adhesion rates on Del-1-deficient murine lung endothelial cells (LEC) than on WT LEC. In order to investigate the role of Del-1 for in vivo homing of PC, we intravenously injected murine fluorescence-labeled WT Lin − bone marrow PC in WT and Del-1 −/− mice 2 days after the induction of hind limb ischemia. Interestingly, the homing of injected Lin − cells to ischemic muscles was significantly increased in Del-1 −/− in comparison to WT mice (200± 30 % increase). Taken together, endogenous Del-1 is a new beta2-integrin ligand, which blocks beta2-integrin-dependent adhesion and homing of PC to ischemic tissues. It is conceivable, that endogenous Del-1 may reduce ischemia-induced neovascularization through an inhibitory effect on the beta2-integrins of progenitor and inflammatory cells.

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