Cell Therapy Abstracts 1

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Intravenous Use of Extract of Liver: Maximal Responses of Reticulocytes from a Single Injection Derived from One Hundred Grams of Liver
            (Castle, 1931) Download
In the early stages of the chemical fractionation of liver, begun in an effort to isolate the active principle effective in pernicious anemia, Cohn, Minot and their associates produced an active extract, the so-called fraction G, which could be readily prepared and was found to be eminently satisfactory in the treatment of pernicious anemia. Later Cohn, 2 West 3 and their respective associates produced numerous experimental fractions, which were given by mouth; but it was not until Cohn was able to prepare fractions which gave no specific …

Human Urine-Derived Stem Cells: Potential for Cell-Based Therapy of Cartilage Defects.
            (Chen et al., 2018) Download
Stem cell therapy is considered an optimistic approach to replace current treatments for cartilage defects. Recently, human urine-derived stem cells (hUSCs), which are isolated from the urine, are studied as a promising candidate for many tissue engineering therapies due to their multipotency and sufficient proliferation activities. However, it has not yet been reported whether hUSCs can be employed in cartilage defects. In this study, we revealed that induced hUSCs expressed chondrogenic-related proteins, including aggrecan and collagen II, and their gene expression levels were upregulated

Cell-based therapies go live.
            (Dove, 2002) Download
Living cells provide the starting material for a cornucopia of new strategies for the treatment of disease, despite several outstanding bureaucratic and technical obstacles

 


Tropical Sprue and Pernicious Anaemia. Aetiology and Treatment.
            (Elders, 1925) Download
Since 1916 the author has been convinced that sprue is a deficiency disease. In many cases the blood picture cannot very well be distinguished from pernicious anaemia, nor can always the tongue changes. In sprue, as in pernicious anaemia, there is often no …

Optimal timing and frequency of bone marrow soup therapy for functional restoration of salivary glands injured by single-dose or fractionated irradiation.
            (Fang et al., 2017) Download
Injections of bone marrow (BM) cell extract, known as 'BM soup', were previously reported to mitigate ionizing radiation (IR) injury to salivary glands (SGs). However, the optimal starting time and frequency to maintain BM soup therapeutic efficacy remains unknown. This study tested the optimal starting time and frequency of BM soup injections in mice radiated with either a single dose or a fractionated dose. First, BM soup treatment was started at 1, 3 or 7 weeks post-IR; positive (non-IR) and negative (IR) control mice received injections of saline (vehicle control). Second, BM soup-treated mice received injections at different frequencies (1, 2, 3 and 5 weekly injections). Third, a 'fractionated-dose radiation' model to injure mouse SGs was developed (5 Gy × 5 days) and compared with the single high dose radiation model. All mice (n = 65) were followed for 16 weeks post-IR. The results showed that starting injections of BM soup between 1 and 3 weeks mitigated the effect of IR-induced injury to SGs and improved the restoration of salivary function. Although the therapeutic effect of BM soup lessens after 8 weeks, it can be sustained by increasing the frequency of weekly injections. Moreover, both single-dose and fractionated-dose radiation models are efficient and comparable in inducing SG injury and BM soup treatments are effective in restoring salivary function in both radiation models. In conclusion, starting injections of BM soup within 3 weeks post-radiation, with 5 weekly injections, maintains 90-100% of saliva flow in radiated mice.

Cell extracts from spleen and adipose tissues restore function to irradiation-injured salivary glands.
            (Fang et al., 2018) Download
A cell extract from whole bone marrow (BM), which we named "BM Soup," has the property to restore saliva secretion to irradiation (IR)-injured salivary glands (SGs). However, BM cell harvesting remains an invasive procedure for the donor. The main objective of this study was to test the therapeutic effect of "Cell Soups" obtained from alternate tissues, such as adipose-derived stromal cells (ADSCs) and spleen cells to repair SGs. BM Soup, Spleen Soup, ADSC Soup, or saline (vehicle control) was injected intravenously into mice with IR-injured SGs (13Gy). Results demonstrated that all three cell soups restored 65-70% of saliva secretion, protected acinar cells, blood vessels, and parasympathetic nerves, and increased cell proliferation. Although protein array assays identified more angiogenesis-related growth factors in ADSC Soup, the length of its therapeutic efficiency on saliva flow was less than that of the BM Soup and Spleen Soup. Another objective of this study was to compare "Fresh" versus "Cryopreserved (-80 °C)" BM Soup. It was found that the therapeutic effect of 12-month "Cryopreserved BM Soup" was comparable to that of "Fresh BM Soup" on the functional restoration of IR-injured SGs. In conclusion, both Spleen Soup and ADSC Soup can be used to mitigate IR-damaged SGs.

 

Agranulocytic Angina Treatment By The Use Of Parenteral And Oral Liver Extract
            (Foran, 1933) Download
The syndrome described by Schultz 1 under the term of agranulocytic angina, and more recently known as malignant neutropenia 2 or pernicious leukopenia, 3 still presents a grave, acute medical emergency for which no highly satisfactory treatment has yet been finally demonstrated. Doan 2 gives the mortality of the untreated cases at 90 plus per cent; of those treated by blood transfusions, at 64 per cent, and of those treated by roentgen irradiation, at 53 per cent. Jackson and his associates 4 report a corrected mortality rate of …

Live Cell Therapy as Potential Risk Factor for Q Fever.
            (George et al., 2017) Download
During an outbreak of Q fever in Germany, we identified an infected sheep flock from which animals were routinely used as a source for life cell therapy (LCT), the injection of fetal cells or cell extracts from sheep into humans. Q fever developed in 7 LCT recipients from Canada, Germany, and the United States.

Xenotransplantation literature update, January/February 2018.
            (Hawthorne and Burlak, 2018) Download
Of late, we have seen a significant increase in the number of re- search articles focused on the outcomes of islet xenotransplantation with addition of a number of primary research and review articles to the field. It would appear that most of the previously perceived barriers to the use of porcine islet cells for transplantation into hu- mans have been addressed and this has been carried out in a number of ways; including genetic modification, immunosuppression, varia- tion of isolation and culture conditions of cells and pre-clinical non- human-primate models with focus on treatment of the vast number of patients suffering from Type 1 diabetes.


Mast cells improve functional recovery of transected peripheral nerve: A novel preliminary study.
            (Ilkhanizadeh et al., 2017) Download
BACKGROUND:  Employment of regenerative properties of cells at the service of nerve repair has been initiated during recent decades. Effects of local transplantation of bone marrow-derived mast cells on peripheral nerve regeneration were studied using a rat sciatic nerve transection model. MATERIALS AND METHODS:  A 10-mm sciatic nerve defect was bridged using a conduit chitosan-based hybrid conduit filled with BMMCs in BMMC group. In positive control group (Pos), the conduit was filled with phosphate-buffered saline alone. The regenerated nerve fibers were studied within 12 weeks after surgery. In sham-operated group, the sciatic nerve was only exposed and manipulated. In negative control (Neg) a 10-mm sciatic nerve defect was created and the nerve stumps were sutured to the adjacent muscles. The regenerated nerve fibers were studied functionally, biomechanically, histologically and immunohiscochemically. RESULTS:  Functional and biomechanical studies confirmed faster recovery of regenerated axons in BMMCs transplanted animals compared to Pos group (p<0.05). Morphometric indices of the regenerated fibers showed that the number and diameter of the myelinated fibers were significantly higher in BMMCs transplanted animals than in Pos group (p<0.05). In immunohistochemistry, location of reactions to S-100 in BMMCs transplanted animals was clearly more positive than that in Pos group. CONCLUSIONS:  BMMCs transplantation could be considered as a readily accessible source of cells that could improve functional recovery of transected sciatic nerve.

Treatment for salivary gland hypofunction at both initial and advanced stages of Sjögren-like disease: a comparative study of bone marrow therapy versus spleen cell therapy with a 1-year monitoring period.
            (Khalili et al., 2014) Download
BACKGROUND AIMS:  Non-obese diabetic mice (NOD) exhibit autoimmune Sjögren-like disease (SS-like). We reported previously that a combined-therapy consisting of immuno- and cell-based therapy rescued NOD from SS-like. However, therapies tested to date on NOD mice were aimed at the initial phase of SS-like. It is unknown whether therapies are effective in restoring salivary function when given at an advanced phase of SS-like. METHODS:  The efficacy of two therapies (bone marrow versus spleen cells) was compared head-to-head for halting/reversing salivary hypofunction at two critical time points of SS-like (7-week-old NOD with normal saliva output and 20-week-old NOD with minimal saliva). NOD mice were divided into four groups: (i) control, (ii) complete Freund's adjuvant (CFA), (iii) bone marrow transplants with CFA or (iv) spleen cell transplants with CFA. Mice were monitored 8-12 months after therapy. RESULTS:  Both cell therapies were effective during the initial phase of SS-like; salivary flow rates were maintained between 80-100% of pre-symptomatic levels. Spleen cell therapy was better than bone marrow when administered in the initial phase of SS-like. When cell therapies were given at an advanced phase of SS-like (20 weeks and older), salivary flow rates improved but were at best 50% of pre-symptomatic levels. Both cell therapies decreased tumor necrosis factor-α, transforming growth factor-β1 levels and T and B cells while increasing epidermal growth factor and regulatory T cells. Elevated serum epidermal growth factor levels were measured in spleen-treated mice. CONCLUSIONS:  A therapeutic effect in advanced phase disease, albeit in mice, holds promise for humans in which Sjögren syndrome is generally not diagnosed until a late stage.

Regenerative medicine: a radical reappraisal of the spleen.
            (Kodama et al., 2005) Download
The spleen has long been considered a dispensable organ. Recent research, however, has found that the spleen of adult mice holds a reservoir of stem cells that can rapidly and robustly differentiate into functional cells of diverse lineages. Splenic stem cells express Hox11, a key embryonic transcription factor that regulates organogenesis. The presence of multi-lineage stem cells in the spleen might represent lifelong persistence of cells from a primitive embryonic region called the aorta-gonad-mesonephros. By bringing together findings from diverse disciplines, we propose that the adult spleen is an important source of multi-lineage stem cells for future cellular therapies for diabetes and other diseases.

Liver therapy in anemia: a motion picture by William P. Murphy
            (Kumar et al., 2006) Download   Movie
On December 10, 1934, the Caroline Institute awarded that year's Nobel Prize in Physiology or Medicine to 3 American investigators: George R. Minot and William P. Murphy of the Harvard Medical School (Boston, MA) and George H. Whipple of the University of Rochester School of Medicine and Dentistry (Rochester, NY),“in recognition of their discoveries respecting liver therapy in anaemias.” On December 12, 1934, Murphy delivered the Nobel Lecture and in the concluding paragraph stated,“Rather than enlarge further upon the …

Local Xenotransplantation of Bone Marrow Derived Mast Cells (BMMCs) Improves Functional Recovery of Transected Sciatic Nerve in Cat: A Novel Approach in Cell Therapy.
            (Mohammadi et al., 2018) Download
Objective:  To determine the effects of bone marrow derived mast cells (BMMCs) on functional recovery of transected sciatic nerve in animal model of cat. Method:  A 20-mm sciatic nerve defect was bridged using a silicone nerve guide filled with BMMCs in BMMC group. In Sham-surgery group (SHAM), the sciatic nerve was only exposed and manipulated. In control group (SILOCONE) the gap was repaired with a silicone nerve guide and both ends were sealed using sterile Vaseline to avoid leakage and the nerve guide was filled with 100 μL of phosphate-buffered saline alone. In cell treated group ([SILOCONE/BMMC) the nerve guide was filled with 100 μL BMMCs (2× 106 cells/100 μL). The regenerated nerve fibers were studied, biomechanically, histologically and immunohiscochemically 6 months later. Results:  Biomechanical studies confirmed faster recovery of regenerated axons in BMMCs transplanted animals compared to control group ( Conclusion:  BMMCs xenotransplantation could be considered as a readily accessible source of cells that could improve recovery of transected sciatic nerve.

The parenteral use of liver extract in pernicious anemia
            (Murphy, 1932) Download
This report deals with the effects of a simple liver extract for parenteral use in the treatment of pernicious anemia. Although many patients with this disease have no great difficulty in consuming sufficient liver to maintain an essentially normal state of health, the introduction of an extract of liver and of stomach substance as a substitute for liver has made the task easier for some of them. There are circumstances, however, in which it may be of distinct importance to have available an actively potent substance which may be given parenterally.A number of papers have appeared recently recording the results of parenteral treatment with various liver extracts in small series of cases. Gänsslen1 in 1930 reported on the successful use of daily intramuscular injections of an extract prepared from 5 Gm. of liver. Similar good results have been reported by Schottmüller,2 van Leeuwen,3 Selander4 and

The spleen--a potential source of new islets for transplantation
            (Robertson et al., 2008) Download
BACKGROUND/PURPOSE:  Islet transplantation offers the potential to reverse diabetes soon after diagnosis and has achieved considerable success in adults. Its use in children has been limited by long-term immunosuppression requirements and donor pancreas shortages. An ideal alternative source of islets would be from autologous precursor cells. The aim of this study was to determine whether the spleen can produce insulin-producing cells (IPCs) in our established model of pancreatic development. METHODS:  Embryonic quail spleens (day 4.5) and chick pancreatic epithelium (day 4) were microdissected and recombined in a ratio of 1:1 (n = 12), 2:1 (n = 9) and 2:2 (n = 5). They were cultured for 7 days, sectioned, and analysed by fluorescent immunochemistry. Controls were performed to ensure clean separation. RESULTS:  Overall, 12 (46%) of 26 recombinants contained IPCs of splenic origin, occurring in 5 (42%) of 12 of the of 1 spleen-1 epithelium recombinants, 3 (33%) of 9 of the 2 spleen-1 epithelium recombinants, and 4 (80%) of 5 of the 2 spleen-2 epithelia recombinants. Controls were negative. CONCLUSIONS:  Preliminary results suggest developing avian spleens can differentiate into IPCs. Increased tissue mass enhanced the likelihood of this occurring. Mesenchyme-to-epithelia ratio did not influence this. The spleen could be an ideal autologous islet source for transplantation in children.

Q fever outbreak among travelers to Germany associated with live cell therapy - United States and Canada, 2014: a co-publication.
            (Robyn et al., 2015) Download
What is already known on this topic?:  Q fever is a zoonotic disease caused by  What is added by this report?:  During September-October 2014, the New York State Department of Health identified Q fever in five patients with exposure to a treatment known as live cell therapy, an alternative medicine practice involving injections of fetal sheep cells, which is a type of xenotransplantation. Investigation revealed that a group of U.S. residents traveled to Germany twice a year to receive this treatment. What are the implications for public health practice?:  Clinicians should consider zoonotic diseases, such as Q fever, in patients whose history includes receipt of a treatment known as live cell therapy. International travel for xenotransplantation procedures can facilitate transmission of zoonotic disease.

New sources of beta-cells for treating diabetes.
            (Sahu et al., 2009) Download
The treatment of diabetes by islet transplantation is presently hampered by the shortage of organ donors. The generation of insulin-producing cells is therefore a major objective in the long-term goal of curing diabetes. Alternative sources of pancreatic beta-cells include existing pancreatic cells, embryonic stem cells, and cells from other tissues such as liver. This commentary considers evidence for two new sources of beta-cells: intrahepatic biliary epithelial cells and gall bladder epithelium. These observations raise the possibility that a patient's own cells may be used as a source of insulin-producing cells for cell replacement in diabetes.

Anemia Therapy: Review Of Various Liver And Stomach Fractions And Iron Salts
            (Teeter, 1945) Download
It has been eighteen years since the announcement of Minot and Murphy 1 of the spectacular beneficial effect of raw liver therapy on patients having addisonian pernicious anemia. In that eighteen years there have been developed many extracts of liver and these extracts have contributed immeasurably to the ease and effectiveness of primary anemia therapy. However, therapy has been somewhat complicated by the multitude of products made available. It has been my experience that this multiplicity of liver extracts leads to …


Niehans 1959 - Cellular Therapy Lectures
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Niehans 1960 - Cellular Therapy
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Niehan 1971 - Cell Therapy Rejuvenation
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Schmid - Cell Therapy
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References

Castle, WB (1931), ‘Intravenous Use of Extract of Liver: Maximal Responses of Reticulocytes from a Single Injection Derived from One Hundred Grams of Liver’, JAMA, 96 (15), 1198-201. PubMed:
Chen, L, et al. (2018), ‘Human Urine-Derived Stem Cells: Potential for Cell-Based Therapy of Cartilage Defects.’, Stem Cells Int, 2018 4686259. PubMed: 29765413
Dove, A (2002), ‘Cell-based therapies go live.’, Nat Biotechnol, 20 (4), 339-43. PubMed: 11923834
Elders, C (1925), ‘Tropical Sprue and Pernicious Anaemia. Aetiology and Treatment.’, Lancet, 205 (5289), 75-77. PubMed:
Fang, D, et al. (2017), ‘Optimal timing and frequency of bone marrow soup therapy for functional restoration of salivary glands injured by single-dose or fractionated irradiation.’, J Tissue Eng Regen Med, PubMed: 28714550
Fang, D, et al. (2018), ‘Cell extracts from spleen and adipose tissues restore function to irradiation-injured salivary glands.’, J Tissue Eng Regen Med, 12 (2), e1289-96. PubMed: 29178627
Foran, FL (1933), ‘Agranulocytic Angina Treatment By The Use Of Parenteral And Oral Liver Extract’, JAMA, 100 (24), 1917-18. PubMed:
George, M, et al. (2017), ‘Live Cell Therapy as Potential Risk Factor for Q Fever.’, Emerg Infect Dis, 23 (7), 1210-12. PubMed: 28296631
Hawthorne, WJ and C Burlak (2018), ‘Xenotransplantation literature update, January/February 2018.’, Xenotransplantation, 25 (2), e12398. PubMed: 29654665
Ilkhanizadeh, B, et al. (2017), ‘Mast cells improve functional recovery of transected peripheral nerve: A novel preliminary study.’, Injury, 48 (7), 1480-85. PubMed: 28532897
Khalili, S, et al. (2014), ‘Treatment for salivary gland hypofunction at both initial and advanced stages of Sjögren-like disease: a comparative study of bone marrow therapy versus spleen cell therapy with a 1-year monitoring period.’, Cytotherapy, 16 (3), 412-23. PubMed: 24411591
Kodama, S, M Davis, and DL Faustman (2005), ‘Regenerative medicine: a radical reappraisal of the spleen.’, Trends Mol Med, 11 (6), 271-76. PubMed: 15949768
Kumar, N, et al. (2006), ‘Liver therapy in anemia: a motion picture by William P. Murphy’, Am Soc Hematology, 107 4970. PubMed:
Mohammadi, R, et al. (2018), ‘Local Xenotransplantation of Bone Marrow Derived Mast Cells (BMMCs) Improves Functional Recovery of Transected Sciatic Nerve in Cat: A Novel Approach in Cell Therapy.’, Bull Emerg Trauma, 6 (2), 108-14. PubMed: 29719840
Murphy (1932), ‘The parenteral use of liver extract in pernicious anemia’, JAMA, 98 (13), 1051-60. PubMed:
Robertson, SA, AM Rowan-Hull, and PR Johnson (2008), ‘The spleen--a potential source of new islets for transplantation’, J Pediatr Surg, 43 (2), 274-78. PubMed: 18280273
Robyn, MP, et al. (2015), ‘Q fever outbreak among travelers to Germany associated with live cell therapy - United States and Canada, 2014: a co-publication.’, Can Commun Dis Rep, 41 (10), 223-26. PubMed: 29769916
Sahu, S, D Tosh, and AA Hardikar (2009), ‘New sources of beta-cells for treating diabetes.’, J Endocrinol, 202 (1), 13-16. PubMed: 19420008
Teeter, EJ (1945), ‘Anemia Therapy: Review Of Various Liver And Stomach Fractions And Iron Salts’, JAMA, 127 (15), 973-76. PubMed: