Localization of Exogenous Mesenchymal Stem Cells in a Pig Model of Lung Transplantation

Background Mesenchymal stem cells (MSCs) have a great potential for the treatment of acute lung injury. This study provides a detailed immunohistochemical and stereological analysis of the localization and distribution of exogenous MSC in a pig model of lung transplantation after intravascular or endobronchial application. Methods MSC derived from human bone marrow were labeled by DiI and administered intravascularly or endobronchially to the lungs of donor pigs after a period of 3 hours warm and 3 hours cold ischemia. The left lung was transplanted to a recipient pig and reperfused for 4 hours before fixation. The right donor lung was fixed for microscopic analysis directly after the ischemia time. Results After both administration routes, a similar number of exogenous MSC was found in the lungs. Within each animal, the heterogeneity of MSC distribution was high both with respect to left and right lung as well as to the different lobes of each lung. After endobronchial application, MSC were found in alveolar and bronchial/bronchiolar lumen, whereas after intravascular administration, they were mainly observed in blood vessels. Conclusion Although the administration of exogenous MSC is possible by endobronchial or intravascular application, it yields a heterogeneous distribution in the lungs which may warrant strategies to improve a more homogeneous distribution.

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130 Burn Injury Reduces Bone Marrow Mesenchymal Stem Cells and Sensitizes Their Adrenergic Receptor Subgroups in a Murine Model

Journal of Burn Care & Research ◽

10.1093/jbcr/irab032.134 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

pp. S87-S88

Author(s):

Kuzhali Muthumalaiappan ◽

Maria Camargo Johnson ◽

Julia Walczak ◽

Vimal Subramaniam ◽

Anthony J Baldea ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Adrenergic Receptor ◽

Burn Injury ◽

Bone Marrow Cells ◽

Ex Vivo ◽

Traumatic Injury ◽

Hematopoietic Cell ◽

The Right

Abstract Introduction Previous burn and traumatic injury studies have established that adrenergic signaling is increased after burn injury and may lead to an impairment of hematopoietic cell development in the bone marrow (BM). Nonetheless, mesenchymal stem cells (MSCs), which have gained momentum in regenerative medicine also play a predominant role in the BM niche. Understanding the propensity of the adrenergic receptor (AR) response by MSCs can be utilized for devising targeted therapies. However, the traditional plastic adherence procedure using ex vivo culture of BM cells for several weeks may skew the actual characteristics of MSCs. Our current study focused on isolating MSCs from freshly obtained BM in a murine scald burn model with a goal to characterize the expression pattern of native AR subgroups present on BM MSCs as compared to sham mice. Methods Eight, two-month-old adult female mice were subjected to a 15% total body 3rd degree burn or sham burn. The mice were sacrificed 7 days later. Femurs were removed and total bone marrow cells were flushed out. Multi parametric flow cytometry was used to gate for cells negative for hematopoietic cell markers (CD45, CD11B) and positive for MSC markers (CD105, CD106, SSEA, Ly6A) and AR subgroups (α1, α2, β1, β2, β3). We measured the number of BM MSCs, quantified the subtypes of ARs present on MSCs, and compared the ratio of AR antibody binding per total MSC population. Results Overall the frequency of MSCs per million total BM cells decreased by 48% post-burn injury with165,300 ± 194 in sham versus 110,000 ± 30 in burn displayed as bar graph in Panel A. Over 90% of MSCs consistently express β2 AR and only 10% express α2 AR subgroup in both scald and sham burn. Presence of other subgroups ranged from 50% to 80% of MSCs as seen in histograms to the right of dotted line in Panel B. Our AR propensity score based on AR mean fluorescence intensity adjusted to total number of MSCs present was increased by 2.8-fold for α1, 2.5-fold for β1, 1.6-fold for β3, and 1.3-fold for β2 AR subgroups (Panel C). These findings indicate burn injury not only decreases the frequency of BM MSCs but also increases the affinity of certain AR subgroups present on MSCs. Since BM MSCs are the major source of cytokines, chemokines and growth factors; detailed studies on AR mediated signaling in BM MSCs is warranted. Conclusions Polarization of AR signaling in BM MSCs by burn-induced catecholamines may have broader implications for comorbidities such as bone resorption and muscle wasting observed in human patients post burn trauma.

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Efficacy of topical and systemic transplantation of mesenchymal stem cells in a rat model of diabetic ischemic wounds

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02288-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jianxin Yan ◽

Jiaji Liang ◽

Yingxuan Cao ◽

Mariya M. El Akkawi ◽

Xuan Liao ◽

...

Keyword(s):

Stem Cells ◽

Wound Healing ◽

Mesenchymal Stem Cells ◽

Chronic Wounds ◽

Blood Perfusion ◽

Systemic Administration ◽

Critical Parameters ◽

Administration Routes ◽

Positive Effects ◽

Systemic Treatments

Abstract Background Mesenchymal stem cells (MSCs) exert positive effects in chronic wounds. However, critical parameters, such as the most effective administration routes, remain unclear. Accordingly, the purpose of this study was to compare the effects of topical and systemic transplantation MSCs on diabetic ischemic wound healing and explored the underlying mechanisms. Method A diabetic ischemic wound model was created on the dorsal foot of type 2 diabetes mellitus (T2DM) rat. Bone marrow-derived mesenchymal stem cells (BM-MSCs) were administered via two routes: topical injection and intravenous (IV) infusion. Wound healing outcomes and blood glucose level were assessed dynamically. Meanwhile, blood flow recovery was evaluated in ischemic gastrocnemius muscles. The homing and transdifferentiation of mKate2-labeled BM-MSCs were assessed by fluorescence imaging and immunohistochemistry (IHC) analysis. Result Both topical and systemic treatments had a positive effect on the diabetic ischemic wound showing a significant reduction in wound area at day 14. Histological results showed an increase in the length of epithelial edges, collagen content, microvessel density in the wound bed, and a higher expression of vascular endothelial growth factor (VEGF). Meanwhile, systemic administration can ameliorate hyperglycemia and improve the blood perfusion of the ischemic hindlimb. BM-MSCs administered systemically were found distributed in wounded tissue and transdifferentiated into endothelial cells. Furthermore, BM-MSCs stimulated angiogenesis at wound sites by downregulating phosphatase and tensin homolog (PTEN) and activation of AKT signaling pathway. Conclusions The results demonstrated that both transplantation delivery method (topical and systemic) of BM-MSCs accelerated wound healing remarkably under pathological conditions. Nevertheless, systemic administration has the potential to ameliorate hyperglycemia and repair the damaged tissue.

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Improved healing of critical-size femoral defect in osteoporosis rat models using 3D elastin/polycaprolactone/nHA scaffold in combination with mesenchymal stem cells

Journal of Materials Science Materials in Medicine ◽

10.1007/s10856-021-06495-w ◽

2021 ◽

Vol 32 (3) ◽

Author(s):

Fatemeh Hejazi ◽

Vahid Ebrahimi ◽

Mehrdad Asgary ◽

Abbas Piryaei ◽

Mohammad Javad Fridoni ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Bone Healing ◽

Critical Size ◽

Therapeutic Potential ◽

Rna Extraction ◽

Osteotomy Site ◽

Cell Groups ◽

The Right

AbstractOsteoporosis is a common bone disease that results in elevated risk of fracture, and delayed bone healing and impaired bone regeneration are implicated by this disease. In this study, Elastin/Polycaprolactone/nHA nanofibrous scaffold in combination with mesenchymal stem cells were used to regenerate bone defects. Cytotoxicity, cytocompatibility and cellular morphology were evaluated in vitro and observations revealed that an appropriate environment for cellular attachment, growth, migration, and proliferation is provided by this scaffold. At 3 months following ovariectomy (OVX), the rats were used as animal models with an induced critical size defect in the femur to evaluate the therapeutic potential of osteogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs) seeded on 3 dimension (3D) scaffolds. In this experimental study, 24 female Wistar rats were equally divided into three groups: Control, scaffold (non-seeded BM-MSC), and scaffold + cell (seeded BM-MSC) groups. 30 days after surgery, the right femur was removed, and underwent a stereological analysis and RNA extraction in order to examine the expression of Bmp-2 and Vegf genes. The results showed a significant increase in stereological parameters and expression of Bmp-2 and Vegf in scaffold and scaffold + cell groups compared to the control rats. The present study suggests that the use of the 3D Elastin/Polycaprolactone (PCL)/Nano hydroxyapatite (nHA) scaffold in combination with MSCs may improve the fracture regeneration and accelerates bone healing at the osteotomy site in rats.

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Contralateral lung transplantation: a left lung implanted in the right thorax

The Annals of Thoracic Surgery ◽

10.1016/s0003-4975(01)02394-3 ◽

2001 ◽

Vol 72 (3) ◽

pp. 933-935 ◽

Cited By ~ 6

Author(s):

Jean-Paul Couetil ◽

Pantelis G Argyriadis ◽

Michael J Tolan ◽

Antoine Achkar ◽

Alain F Carpentier

Keyword(s):

Lung Transplantation ◽

Left Lung ◽

Contralateral Lung ◽

The Right

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Abstract 587: A Randomized Study Evaluating Outcomes of Cardiopulmonary Resuscitation in Rats with Myocardial Infarction Treated with Three Delivery Methods of Mesenchymal Stem Cells

Circulation ◽

10.1161/circ.118.suppl_18.s_585 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Tong Wang ◽

Zhi Wan ◽

Wanchun Tang ◽

Shijie Sun ◽

Zitong Huang ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cardiopulmonary Resuscitation ◽

Survival Time ◽

Myocardial Function ◽

Left Ventricular ◽

Left Ventricular Cavity ◽

Intramyocardial Injection ◽

Administration Routes

We investigated the effect of allogeneic mesenchymal stem cells (MSCs) on myoardial function following cardiopulmonary resuscitation (CPR) in a rat model of myocardial infarction. We further investigated the efficacy of three routes of MSCs administration including intravenous, intraventricular and intramyocardial injection. Regardless of administration routes, MSCs would improve myocardial function after CPR in myocardial infarction animals. Myocardial infarction was induced by ligation of the left anterior descending coronary artery in 54 rats (6 groups, 9 rats for each). One month later, animals were randomized to receive injection of 5×10 6 MSCs labeled with PKH26 or PBS alone as a placebo into right femoral vein or left ventricular cavity or the infarction zone in the anterior ventricular free wall. Four weeks after injection, 6 minutes of untreated ventricular fibrillation (VF) followed by 6 minutes of CPR were performed prior to defibrillation. Hemodynamics, including cardiac index (CI), dp/dt40, −dp/dt and left ventricular diastolic pressure(LVDP) were measured before induction of VF (baseline) and hourly following resuscitation. There were siginificant improvements in CI, dp/dt40(Figure 1 ), −dp/dt, LVDP after CPR in MSCs treated animals, regardless of the sites of injection. Survival time after CPR was siginificantly increased in MSCs trearted groups comparing with the corresponding PBS treated groups. Independent of administration routes, myocardial function and survival time after CPR were comparably improved in all groups treated with MSCs in constrast to the PBS groups. Figure 1

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174 Use of mesenchymal stem cell treatment to improve oocyte yield and invitro embryo production in cattle

Reproduction Fertility and Development ◽

10.1071/rdv32n2ab174 ◽

2020 ◽

Vol 32 (2) ◽

pp. 214

Author(s):

M. Peixer ◽

P. Malard ◽

J. Carvalho ◽

M. Dode ◽

J. Viana ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Repeated Measures ◽

Treatment Time ◽

Left Ovary ◽

Saline Control ◽

Embryo Production ◽

Oocyte Yield ◽

The Right ◽

Phosphate Buffered Saline

Cumulative tissue damage and chronic inflammation associated with frequent ovum pickup (OPU) may lead to a progressive reduction in the number and quality of the oocytes recovered, particularly in donors with a high antral follicle count. The aim of this study was to evaluate the effect of an intraovarian treatment with mesenchymal stem cells (MSC) on oocyte yield, quality, and development potential during invitro embryo production (IVEP) in cattle donors undergoing repeated OPU. Mesenchymal stem cells were previously isolated from adipose tissue, cultured in Dulbecco's modified Eagle medium until reaching 80% confluence, isolated with trypsin, and frozen in liquid N2 until use. Characterisation of MSC was carried out according to the guidelines of the International Society for Cellular Therapy. Nelore (Bos indicus) cows (n=5) were used in this study, with the ovaries as replicates. The cows underwent eight OPU sessions at 15-day intervals, and the oocytes recovered were graded and used for IVEP with the semen of a single sire and batch under similar invitro culture conditions. To ensure a high inflammatory response, immediately after the fourth OPU session all ovaries received 30 additional punctures, performed with a 16-gauge Jelco needle. Six hours later, the left ovary of each cow was injected with 500µL of Dulbecco's modified phosphate buffered saline (control ovary) and the right ovary received 500µL of Dulbecco's modified phosphate buffered saline with 2.5×106 allogenic MSC (treated ovary). Oocyte yield and embryo production before and after treatment were recorded for each ovary and donor. Grade I blastocysts produced from control and treated ovaries were used for gene expression evaluation. Data was analysed using the repeated-measures procedure of SAS (SAS Institute Inc.) to account for the effects of treatment, time, and interactions. There was no difference (P>0.05) in any endpoint before treatment (sessions 1-4) between the right and left ovaries. Thus, differences between ovaries observed in OPU sessions 5-8 were assumed to be due to the treatment. After the injection of MSC, more total and viable oocytes were collected from the right ovaries compared with the left ovaries (15.3±2.2 vs. 8.7±1.2 (P<0.02) and 13.6±2.1 vs. 7.1±1.0 (P<0.01), respectively), resulting in more embryos produced invitro (7.6±1.2 vs. 3.6±0.6, respectively; P<0.01) as well as more initial and expanded blastocysts (1.4±0.3 vs. 0.4±0.1 and 4.4±0.9 vs. 2.1±0.4, respectively; P<0.04). The proportion of viable oocytes recovered from the right ovary after treatment was greater than that from the left ovary (89.1% vs. 81.5%; P<0.05). However, blastocyst rates did not differ between ovaries before or after treatment (50.4% vs. 55.5%: P>0.05). In the blastocysts produced from treated ovaries, SLC2A3 was overexpressed (P<0.04), whereas there was no difference for the expression of KRT8, PLAC8, SLC2A1, CASP3, PRDX3, or SOD2 (P>0.05), suggesting potential differences in glucose uptake and metabolism. In conclusion, intraovarian treatment with MSC improved oocyte yield and quality and may be an alternative to increase IVEP from donors under intensive OPU schedules. This research was supported by CNPq, CAPES, and Fazenda Grupo Esplanada.

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Bone marrow mononuclear cells versus mesenchymal stem cells from adipose tissue on bone healing in an Old World primate: can this be extrapolated to humans?

Arquivo Brasileiro de Medicina Veterinária e Zootecnia ◽

10.1590/1678-4162-10362 ◽

2019 ◽

Vol 71 (3) ◽

pp. 917-928

Author(s):

E. Branco ◽

C.M.F.C. Miranda ◽

A.R. Lima ◽

K.S.M. Silva ◽

R.M. Cabral ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Adipose Tissue ◽

Iliac Crest ◽

Mononuclear Cells ◽

Bone Marrow Mononuclear Cells ◽

Old World ◽

Bone Injury ◽

The Right

ABSTRACT In veterinary medicine, the cell therapy is still unexplored and there are many unanswered questions that researchers tend to extrapolate to humans in an attempt to treat certain injuries. Investigating this subject in nonhuman primates turns out to be an unparalleled opportunity to better understand the dynamics of stem cells against some diseases. Thus, we aimed to compare the efficiency of bone marrow mononuclear cells (BMMCs) and mesenchymal stem cells (MSCs) from adipose tissue of Chlorocebus aethiops in induced bone injury. Ten animals were used, male adults subjected, to bone injury the iliac crests. The MSCs were isolated by and cultured. In an autologous manner, the BMMCs were infused in the right iliac crest, and MSCs from adipose tissue in the left iliac crest. After 4.8 months, the right iliac crests fully reconstructed, while left iliac crest continued to have obvious bone defects for up to 5.8 months after cell infusion. The best option for treatment of injuries with bone tissue loss in old world primates is to use autologous MSCs from adipose tissue, suggesting we can extrapolate the results to humans, since there is phylogenetic proximity between species.

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Mesenchymal stem cells modulate the gene expression of T- type Calcium Channel Subunit Alpha 1G (Cav3.1) in acute phase of epilepsy

10.5327/1516-3180.709 ◽

2021 ◽

Author(s):

Vitoria Pimentel da Silva ◽

Laura Provenzi ◽

Nicole Becker ◽

Giovani Zocche ◽

Gabriel Leal ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Calcium Channel ◽

Calcium Influx ◽

Control Group ◽

Administration Routes ◽

Therapeutic Alternatives ◽

And Control ◽

The Brain

Introduction: Temporal Lobe Epilepsy (TLE) is a disorder caused by neuronal electrical imbalance, clinically manifested by spontaneous and recurrent seizures1,2. Its pathogenesis involves channelopathies of calcium channels, which contributes to hyperexcitability and hypersynchrony in TLE3 . About 30% of patients do not respond to drug treatment4 , making it necessary to develop new therapeutic alternatives, such as cell therapy. This work aimed to evaluate the modulation of mesenchymal stem cells (MSCs) in the calcium channel CACNA1G (Cav3.1) gene expression. Methods: MSCs were extracted from Wistar rats bone marrow and then cultured and transplanted intravenously and intranasally in the control and epileptic groups. The brain was collected 1 and 7 days after transplantation to analyze gene expression. Results: The analysis showed that treated animals had greater gene expression, compared to animals not treated in the epileptic and control group, in both days and administration routes. Furthermore, epileptic animals that were not treated had a low or negative expression of the gene. The epileptic rats that were treated, on the other hand, had a marked increase in gene expression e in the prefrontal cortex. Conclusion: This up-regulation noted on the treated groups raises the hypothesis that MSCs would be using these channels to modify the microenvironment5 , intensifying Cav.3.1 transcription and contributing to tissue regeneration by neurodifferentiation6,7. This is supported by the increase in the calcium influx present in the early stages of neuronal maturation8,9. Thus, MSCs can modulate gene expression in the pilocarpine-induced animal’s brain, making Cav3.1 a target to be explored in epilepsy.

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REPAIR OF SCIATIC NERVE LESION AUGMENTED WITH AMNION MEMBRANE COMPOSITE AND MESENCHYMAL STEM CELL

(JOINTS) Journal Orthopaedi and Traumatology Surabaya ◽

10.20473/joints.v9i1.2020.29-33 ◽

2020 ◽

Vol 9 (1) ◽

pp. 29

Author(s):

Heri Suroto ◽

R. Taufan Mulyo Wibisono

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Sciatic Nerve ◽

Amniotic Membrane ◽

Nerve Repair ◽

Penetrating Trauma ◽

Sensory Function ◽

Nerve Lesion ◽

Foot Function ◽

The Right

Background: Peripheral nerve injuries (PNI) are quite common, with an incidence of 13.9% per 100,000 people per year. The most cause is direct penetrating trauma. PNI will cause a significant decrease in the quality of life of patients.Case: A 21-years-old woman complained of the inability to move her right leg and numbness. She had been injured in the of the right thigh due to broken glass. The patient underwent emergency surgery to repair the right Femoral artery and the Sciatic nerve.Discussion: After six months since the first operation, flail foot and anesthesia were persisting with a FADI score of 47.1. We decided to perform re-exploration, from the exploration we found neuroma on the sciatic nerve. Excision was performed on the Neuroma then an end-to-end anastomosis was performed on both sciatic nerve components (tibial and peroneal) and augmented using amniotic membrane composites and mesenchymal stem cells. After 6 months since the second surgery, the patient could perform ankle dorsal flexion. After 12 months postoperatively, the patient could move his right leg functionally, sensory function also improved. Patients can undergo daily activities without difficulty, with a FADI score of 96.2. Conclusion: There is a significant improvement in the patient's foot function after surgery using the method we used, more research is needed to optimize the use of amniotic membrane and mesenchymal stem cells as augmentation in nerve repair.

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Therapeutic Applications of Mesenchymal Stem Cells in Idiopathic Pulmonary Fibrosis

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.639657 ◽

2021 ◽

Vol 9 ◽

Author(s):

Shengnan Yang ◽

Peipei Liu ◽

Yale Jiang ◽

Zai Wang ◽

Huaping Dai ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Interstitial Lung Disease ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Lung Disease ◽

Complex Disease ◽

Unknown Etiology ◽

Epithelial Tissue ◽

Administration Routes

Idiopathic pulmonary fibrosis (IPF) is an interstitial disease of unknown etiology characterized by progressive pulmonary fibrosis. Pirfenidone and nintedanib are the only drugs that can prolong the time to disease progression, slow down the decline in lung function, and prolong survival. However, they do not offer a cure and are associated with tolerability issues. The pluripotency of mesenchymal stem cells (MSCs) and their ability to regulate immunity, inhibit inflammation, and promote epithelial tissue repair highlight the promise of MSC therapy for treating interstitial lung disease. However, optimal protocols are lacking for multi-parameter selection in MSC therapy. This review summarizes preclinical studies on MSC transplantation for the treatment of interstitial lung disease and clinical studies with known results. An analysis of relevant factors for the optimization of treatment plans is presented, including MSCs with different sources, administration routes and timing, dosages, frequencies, and pretreatments with MSCs. This review proposes an optimized plan for guiding the design of future clinical research to identify therapeutic options for this complex disease.

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