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Scientific Articles by our Scientists

Autologous Stromal Vascular Fraction Cells: A Tool for Facilitating Tolerance in Rheumatic Disease

Accepted Manuscript, April 6, 2010
Thomas E. Ichim, Robert J. Harman, Wei-Ping Min, Boris Minev, Fabio Solano, Jorge Paz Rodriguez, Doru T Alexandrescu, Rosalia De Necochea-Campion, Xiang Hu, Annette M Marleau, Neil H Riordan

This is a PDF file of an unedited manuscript that has been accepted for publication in Cellular Immunology. As a service we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Mesenchymal Stem Cells as Anti-inflammatories: Implications for Treatment of Duchenne Muscular Dystrophy

Accepted Manuscript, October 13, 2009
Thomas E. Ichim, Doru T. Alexandrescu, Fabio Solano, Fabian Lara, Rosalia De Necochea Campion, Eugenia Paris, Erik J Woods, Michael P Murphy, Constantin A. Dasanu, Amit N Patel, Annette M Marleau, Neil H. Riordan

This is a PDF file of an unedited manuscript that has been accepted for publication in Cellular Immunology. As a service we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis

April 24, 2009
Riordan NH, Ichim TE, Min WP, Wang H, Solano F, Lara F, Alfaro M, Rodriguez JP, Harman RJ, Patel AN, Murphy MP, Lee RR, Minev B.
Medistem Inc, San Diego, CA, USA.

The stromal vascular fraction (SVF) of adipose tissue is known to contain mesenchymal stem cells (MSC), T regulatory cells, endothelial precursor cells, preadipocytes, as well as anti-inflammatory M2 macrophages. Safety of autologous adipose tissue implantation is supported by extensive use of this procedure in cosmetic surgery, as well as by ongoing studies using in vitro expanded adipose derived MSC. Equine and canine studies demonstrating anti-inflammatory and regenerative effects of non-expanded SVF cells have yielded promising results. Although non-expanded SVF cells have been used successfully in accelerating healing of Crohn's fistulas, to our knowledge clinical use of these cells for systemic immune modulation has not been reported. In this communication we discuss the rationale for use of autologous SVF in treatment of multiple sclerosis and describe our experiences with three patients. Based on this rationale and initial experiences, we propose controlled trials of autologous SVF in various inflammatory conditions.

PMID: 19393041 [PubMed - indexed for MEDLINE] PMCID: PMC2679713

Feasibility investigation of allogeneic endometrial regenerative cells.

February 20, 2009
Zhong Z, Patel AN, Ichim TE, Riordan NH, Wang H, Min WP, Woods EJ, Reid M, Mansilla E, Marin GH, Drago H, Murphy MP, Minev B.
Medistem Inc, San Diego, USA.

Endometrial Regenerative Cells (ERC) are a population of mesenchymal-like stem cells having pluripotent differentiation activity and ability to induce neoangiogenesis. In vitro and animal studies suggest ERC are immune privileged and in certain situations actively suppress ongoing immune responses. In this paper we describe the production of clinical grade ERC and initial safety experiences in 4 patients with multiple sclerosis treated intravenously and intrathecally. The case with the longest follow up, of more than one year, revealed no immunological reactions or treatment associated adverse effects. These preliminary data suggest feasibility of clinical ERC administration and support further studies with this novel stem cell type.

PMID: 19232091 [PubMed - indexed for MEDLINE] PMCID: PMC2649897

Inhibition of intracranial glioma growth by endometrial regenerative cells. (15 February, 2009)

February 15, 2009
Han X, Meng X, Yin Z, Rogers A, Zhong J, Rillema P, Jackson JA, Ichim TE, Minev B, Carrier E, Patel AN, Murphy MP, Min WP, Riordan NH.
Bio-Communications Research Institute, Wichita, Kansas, USA

Animal studies have demonstrated that selective tropism of mesenchymal stem cells (MSC) for glioma may be used as a means of selective delivery of cytotoxic payloads. Endometrial Regenerative Cells (ERC) are a population of mesenchymal-like cells which possesse pluripotent differentiation capacity and is characterized by unique surface markers and growth factor production. In this study we sought to determine whether unmanipulated ERC would alter the growth of glioma using the aggressive C6/LacZ7 (C6) into Sprague Dawley rat model. ERC administration by intravenous (i.v.) or intratumoral (i.t.) showed significant inhibition of glioma: volume reduction of 49% after i.v. treatment (p < 0.05), and about 46% i.t. treatment (p < 0.05). Tumor reduction was associated with inhibition of angiogenesis and reduced numbers of CD133 positive cells in the incranial tumor. Despite the angiogenic potential of ERC in the hindlimb ischemia model, these data support a paradoxical tumor inhibitory activity of ERC. Further studies are needed to determine the qualitative differences between physiological angiogenesis, which seems to be supported by ERC and tumor angiogenesis which appeared to be inhibited.

PMID: 19197154 [PubMed - indexed for MEDLINE]

Allogeneic endometrial regenerative cells: an "Off the shelf solution" for critical limb ischemia?

August 19, 2008
Murphy MP, Wang H, Patel AN, Kambhampati S, Angle N, Chan K, Marleau AM, Pyszniak A, Carrier E, Ichim TE, Riordan NH.
Division of Vascular Surgery, Indiana University School of Medicine, Indiana, USA.

Critical limb ischemia (CLI) is an advanced form of peripheral artery disease which is responsible for approximately 100,000 amputations per year in the US. Trials to date have reported clinical improvement and reduced need for amputation in CLI patients receiving autologous bone marrow or mobilized peripheral blood stem cells for stimulation of angiogenesis. While such treatments are currently entering Phase III trials, practical and scientific pitfalls will limit widespread implementation if efficacy is proven. Hurdles to be overcome include: a) reduced angiogenic potential of autologous cells in aged patients with cardiovascular risk factors; b) invasiveness/adverse effects of bone marrow extraction and G-CSF mobilization, respectively; and c) need for on-site cellular manipulation. The Endometrial Regenerative Cell (ERC) is a mesenchymal-like stem cell derived from the menstrual blood that is believed to be associated with endometrial angiogenesis. We discuss the possibility of using allogeneic ERCs as an "off the shelf" treatment for CLI based on the following properties: a) High levels of growth factors and matrix metalloprotease production; b) Ability to inhibits inflammatory responses and lack of immunogenicity; and c) Expandability to great quantities without loss of differentiation ability or karyotypic abnormalities.

PMID: 18713449 [PubMed - indexed for MEDLINE]

Immune effects of mesenchymal stem cells: implications for Charcot-Marie-Tooth disease.

June 4, 2008
Leal A, Ichim TE, Marleau AM, Lara F, Kaushal S, Riordan NH.
School of Biology and Neuroscience Research Program, University of Costa Rica, San José, Costa Rica, USA.

Mesenchymal stem cell (MSC) therapy is the most clinically advanced form of cell therapy, second to hematopoietic stem cell transplants. To date, MSC have been used for immune modulation in conditions such as Graft Versus Host Disease (GVHD) and Crohn's Disease, for which Phase III clinical trials are currently in progress. Here, we review the immunological properties of MSC and make a case for their use in treatment of Charcot-Marie-Tooth disease type 1 (CMT1), a group of inherited peripheral neuropathies. CMT1 is characterized by demyelination and aberrant immune activation making this condition an ideal target for exploration of MSC therapy, given the ability of these cells to promote sheath regeneration as well as suppress inflammation. Studies supporting this hypothesis will be presented and placed into the context of other cell-based approaches that are theoretically feasible. Given that MSCs selectively home to areas of inflammation, as well as exert effects in an allogeneic manner, the possibility of an "off the shelf" therapy for CMT1 will be discussed.

PMID: 18627903 [PubMed - indexed for MEDLINE]

Antigen-specific therapy of rheumatoid arthritis

February 8, 2008
Ichim TE, Zheng X, Suzuki M, Kubo N, Zhang X, Min LR, Beduhn ME, Riordan NH, Inman RD, Min WP.
University of Western Ontario, Departments of Surgery, Pathology, Microbiology & Immunology, 339 Windermere Road, University Hospital C9-136, London, Ontario, N6A 5A5, Canada.

Immunotherapy offers the promise of antigen-specific suppression of pathological immune responses in conditions such as autoimmunity and organ transplantation. Substantial advances have been made in recent years in terms of understanding basic immunological mechanisms of autoreactivity, as well as clinically implementing immune-based therapies that are antigen nonspecific. OBJECTIVE: To provide an integrated overview of the current state of the art in terms of antigen-specific tolerance induction, as well as to predict future directions for the field. METHODS: Examples of successes and failures of antigen-specific immunotherapy were sought. Particular attention was paid to the well-established collagen II-induced model of arthritis. RESULTS/CONCLUSIONS: Previous failures of antigen-specific immunotherapy were associated with lack of identification of clinically relevant antigens, as well as inappropriate tolerogenic methodologies. The advances in proteomics combined with novel gene-specific immune modulatory techniques place today's translational researchers in a unique position to tackle the problem of antigen-specific immunotherapeutic protocols.

PMID: 18194075 [PubMed - indexed for MEDLINE]

Endometrial regenerative cells: a novel stem cell population)

November 15, 2007
Meng X, Ichim TE, Zhong J, Rogers A, Yin Z, Jackson J, Wang H, Ge W, Bogin V, Chan KW, Thébaud B, Riordan NH.
Bio-Communications Research Institute, Wichita, USA,

Angiogenesis is a critical component of the proliferative endometrial phase of the menstrual cycle. Thus, we hypothesized that a stem cell-like population exist and can be isolated from menstrual blood. Mononuclear cells collected from the menstrual blood contained a subpopulation of adherent cells which could be maintained in tissue culture for >68 doublings and retained expression of the markers CD9, CD29, CD41a, CD44, CD59, CD73, CD90 and CD105, without karyotypic abnormalities. Proliferative rate of the cells was significantly higher than control umbilical cord derived mesenchymal stem cells, with doubling occurring every 19.4 hours. These cells, which we termed "Endometrial Regenerative Cells" (ERC) were capable of differentiating into 9 lineages: cardiomyocytic, respiratory epithelial, neurocytic, myocytic, endothelial, pancreatic, hepatic, adipocytic, and osteogenic. Additionally, ERC produced MMP3, MMP10, GM-CSF, angiopoietin-2 and PDGF-BB at 10-100,000 fold higher levels than two control cord blood derived mesenchymal stem cell lines. Given the ease of extraction and pluripotency of this cell population, we propose ERC as a novel alternative to current stem cells sources.

PMID: 18005405 [PubMed - indexed for MEDLINE]

Stem cell therapy for autism

June 27, 2007
Ichim TE, Solano F, Glenn E, Morales F, Smith L, Zabrecky G, Riordan NH.
Medistem Laboratories Inc, Tempe, Arizona, USA.

Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions whose incidence is reaching epidemic proportions, afflicting approximately 1 in 166 children. Autistic disorder, or autism is the most common form of ASD. Although several neurophysiological alterations have been associated with autism, immune abnormalities and neural hypoperfusion appear to be broadly consistent. These appear to be causative since correlation of altered inflammatory responses, and hypoperfusion with symptology is reported. Mesenchymal stem cells (MSC) are in late phases of clinical development for treatment of graft versus host disease and Crohn's Disease, two conditions of immune dysregulation. Cord blood CD34+ cells are known to be potent angiogenic stimulators, having demonstrated positive effects in not only peripheral ischemia, but also in models of cerebral ischemia. Additionally, anecdotal clinical cases have reported responses in autistic children receiving cord blood CD34+ cells. We propose the combined use of MSC and cord blood CD34+cells may be useful in the treatment of autism.

PMID: 17597540 [PubMed]

Placental mesenchymal and cord blood stem cell therapy for dilated cardiomyopathy. (14 April, 2007)

Ichim TE, Solano F, Brenes R, Glenn E, Chang J, Chan K, Riordan NH.
Medistem Laboratories Inc., 2027 E Cedar Street Suite 102, Tempe, AZ 85281, USA.

Regenerative treatment of dilated, non-ischaemic cardiomyopathy represents a significant unmet clinical need. Intracoronary administration of autologous bone marrow stem cells has demonstrated positive results in treatment of post-infarct and chronic ischaemic patients. Limitations of this procedure include: invasiveness of bone marrow extraction and cardiac catheterization, and dependence on stem cell populations that are aged and possibly senescent. Here, the use of intravenously administered allogeneic placental matrix derived mesenchymal stem cells for treatment of dilated cardiomyopathy is discussed. Safety of this cell population has already been established in completed Phase I and II trials; however, to date, clinical implementation for dilated cardiomyopathy has not been reported. Preclinical studies have demonstrated that mesenchymal stem cells: (i) inhibit myocardial inflammation; (ii) inhibit cardiomyocyte apoptosis; (iii) stimulate angiogenesis; and (iv) display therapeutic activity in models of dilated cardiomyopathy. Clinical studies have demonstrated the ability of mesenchymal stem cells to inhibit post-infarct remodelling, as well as potently block inflammatory processes in graft versus host and Crohn disease. Presented here is case report of a patient with dilated cardiomyopathy treated with intravenous allogeneic mesenchymal stem cells and expanded umbilical cord blood CD34 cells who underwent a profound clinical improvement.

PMID: 18549704 [PubMed - indexed for MEDLINE]

Cord blood in regenerative medicine: do we need immune suppression?

January 30, 2007)
Riordan NH, Chan K, Marleau AM, Ichim TE.
Medistem Laboratories Inc, Tempe, Arizona, USA.

Cord blood is currently used as an alternative to bone marrow as a source of stem cells for hematopoietic reconstitution after ablation. It is also under intense preclinical investigation for a variety of indications ranging from stroke, to limb ischemia, to myocardial regeneration. A major drawback in the current use of cord blood is that substantial morbidity and mortality are associated with pre-transplant ablation of the recipient hematopoietic system. Here we raise the possibility that due to unique immunological properties of both the stem cell and non-stem cell components of cord blood, it may be possible to utilize allogeneic cells for regenerative applications without needing to fully compromise the recipient immune system. Issues raised will include: graft versus host potential, the immunogenicity of the cord blood graft, and the parallels between cord blood transplantation and fetal to maternal trafficking. The previous use of unmatched cord blood in absence of any immune ablation, as well as potential steps for widespread clinical implementation of allogeneic cord blood grafts will also be discussed.

PMID: 17261200 [PubMed]


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