Stem Cell Research Publications

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Autologous Stromal Vascular Fraction Therapy for Rheumatoid Arthritis: Rationale and Clinical Safety

Paz Rodriguez J, Murphy M, Hong S, Madrigal M, March K, Minev B, Harman R, Chen CS, Berrocal Timmons R, Marleau A, Riordan N – International Archives of Medicine 2012, 5:5

Advancements in rheumatoid arthritis (RA) treatment protocols and introduction of targeted biological therapies have markedly improved patient outcomes, despite this, up to 50% of patients still fail to achieve a significant clinical response. In veterinary medicine, stem cell therapy in the form of autologous stromal vascular fraction (SVF) is an accepted therapeutic modality for degenerative conditions with 80% improvement and no serious treatment associated adverse events reported. Clinical translation of SVF therapy relies on confirmation of veterinary findings in targeted patient populations. Here we describe the rationale and preclinical data supporting the use of autologous SVF in treatment of RA, as well as provide 1, 3, 6, and 13 month safety outcomes in 13 RA patients treated with this approach.

Could Metabolic Syndrome, Lipodystrophy, and Aging Be Mesenchymal Stem Cell Exhaustion Syndromes?

Eduardo Mansilla,* Vanina Díaz Aquino, Daniel Zambón, Gustavo Horacio Marin, Karina Mártire, Gustavo Roque, Thomas Ichim, Neil H. Riordan, Amit Patel, Flavio Sturla, Gustavo Larsen, Rubén Spretz, Luis Núñez, Carlos Soratti, Ricardo Ibar, Michiel van Leeuwen, José María Tau, Hugo Drago, and Alberto Maceira – Stem Cells Int. 2011; 2011: 943216

One of the most important and complex diseases of modern society is metabolic syndrome. This syndrome has not been completely understood, and therefore an effective treatment is not available yet. We propose a possible stem cell mechanism involved in the development of metabolic syndrome. This way of thinking lets us consider also other significant pathologies that could have similar etiopathogenic pathways, like lipodystrophic syndromes, progeria, and aging. All these clinical situations could be the consequence of a progressive and persistent stem cell exhaustion syndrome (SCES). The main outcome of this SCES would be an irreversible loss of the effective regenerative mesenchymal stem cells (MSCs) pools. In this way, the normal repairing capacities of the organism could become inefficient. Our point of view could open the possibility for a new strategy of treatment in metabolic syndrome, lipodystrophic syndromes, progeria, and even aging: stem cell therapies.

Feasibility of combination allogeneic stem cell therapy for spinal cord injury: a case report

Thomas E. Ichim, Fabio Solano, Fabian Lara, Eugenia Paris, Federico Ugalde, Jorge Paz Rodriguez,
Boris Minev, Vladimir Bogin, Famela Ramos, Erik J Woods, Michael P Murphy, Amit N Patel,
Robert J Harman, Neil H. Riordan – International Archives of Medicine 2010, 3:30

Cellular therapy for spinal cord injury (SCI) is overviewed focusing on bone marrow mononuclear cells, olfactory ensheathing cells, and mesenchymal stem cells. A case is made for the possibility of combining cell types, as well as for allogeneic use.

Combination of Stem Cell Therapy for Heart Failure

Ichim T, Solano F, Lara F, Paz Rodriguez J, Cristea O, Minev B, Ramos F, Woods E, Murphy M, Alexandrescu D, Patel A, Riordan N. – International Archives of Medicine 2010; 3:5

Patients with congestive heart failure that are not eligible for transplantation have limited therapeutic options. Stem cell therapy such as autologous bone marrow, mobilized peripheral blood, or purified cells thereof has been used clinically since 2001. To date over 1000 patients have received cellular therapy as part of randomized trials, with the general consensus being that a moderate but statistically significant benefit occurs. These papers discuss increasing stem cells migration to the heart, augmenting stem cell activity and combining existing stem cell therapies to recapitulate a therapeutic niche.

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

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 – Accepted Manuscript 2010; Cellular Immunology

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 mechanism of auto reactivity, as well as clinically implementing immune based therapies that are antigen nonspecific.

Immune Effects of Mesenchymal Stem Cells: Implications for Charcot-Marie-Tooth Disease

Alejandro Leal, Thomas E. Ichim, Annette M. Marleau, Fabian Lara, Shalesh Kaushal, Neil H. Riordan – Cellular Immunology 2008; 253: 11-15

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.

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

Ichim T, Alexandrescu D, Solano F, Lara F, De Necochea R, Paris E, Woods E, Murphy M, Dasanu C, Patel A, Marleau A, Leal A, Riordan N. – Cellular Immunology 2010; 260: 75-82

Duchenne muscular Dystrophy is a lethal X linked musculodegenerative condition consisting of a n underlying genetic defect whose manifestation is augmented by inflammatory mechanism. Previous treatment approaches using gene replacement have been relatively unsuccessful. The only intervention to mediate improvement in survival is glucocorticoid treatment. Given this modality appears to function via suppression of underlying inflammation; we focus this review on the inflammatory response as a target for mesenchymal stem cell therapy.

In contrast to other cell based therapies attempted in DMD, MSC have the advantages of ability to fuse with and genetically complement dystrophic muscle, possess anti inflammatory activities and produce trophic factors that might augment activity of endogenous repair cells.

Non-expanded Adipose Stromal Vascular Fraction Cell Therapy for Multiple Sclerosis

Riordan N, Ichim T, Min W, Wang H, Solano F, Lara F, Alfaro M, Paz Rodriguez J, Harman R, Patel A, Murphy M, Lee R, Minev B. – Journal of Translational Medicine. 2009; 7:29

The stromal vascular fraction of adipose tissue is known to contain mesenchymal stem cells, T regulatory cells, endothelial precursors 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.

Multiple sclerosis is an autoimmune condition in which the immune system attacks the central nervous system, leading to demyelinization. It may cause numerous physical and mental symptoms, and often progresses to physical and cognitive disability.

Here we presented 3 cases of MS patients treated with SVF adipose fraction and their histories.

Inhibition of Intracranial Glioma Growth by Endometrial Regenerative Cells

Han X, Meng X, Yin Z, Rogers A, Zhong J, Rllema P, Jackson J, Ichim T, Minev B, Carrier E, Patel A, Murphy M, Min W, Riordan N – Cell Cycle 2009; 8 (4)

Endometrial regenerative cells are a population of endometrial derived stem cells having hability to differentiate into numerous non hematopoietic tissues. Given the ease of the collection, ability for large scale expansion and lack of need for tissue marching to achieve therapeuthic effects, a clinical translation program was initiated to the goal of developing an off the shelf theraphy for critical limb ischemia.

In our experiments we observed a profound inhibition C6 glioma cells in animals treated with ERC. Suppression of tumor growth was not associated with necrosis but characterize by lower number of new blood vessels.

Feasibility Investigation of Allogeneic Endometrial Regenerative Cells

Zhong Z, Patel A, Ichim T, Riordan N, Wang H, Min W, Woods E, Reid M, Mansilla E, Marin G, Drago H, Murphy M, Minev B – Journal of translational Medicine 2009; 7:15

Endometrial regenerative cells (ERC) are a population of mesenchymal like stem cells having pluripotent differentiation activity and ability to induce neoangiogenesis (new blood vessel formation). 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 if clinical grade ERC and initial safety experience in 4 patients with multiple sclerosis treated intravenously and intrathecally. The case with the longest follow up, up to one year, revealed no immunological reactions or treatment associated adverse effects. This paper demonstrates for the first time feasibility of administration of ERC based cell therapy in four patients with MS. This off the shelf allogenic ERC treatment could conceptually have several positive aspects such as ease of administration, ability to use optimized cells and administration of multiple doses.

Circulating Endothelial Progenitor Cells: A New Approach to Anti-aging Medicine

Mikirova N, Jackson J, Hunninghake R, Kenyon J, Chan K, Swindlehurst C, Minev B, Patel A, Murphy M, Smith L,Alexandrescu D, Ichim T, Riordan N. – Journal of Translational Medicine 2009; 7:106

Endothelial dysfunction is associated with mayor causes of morbidity and mortality, as well as numerous age related conditions. The possibility of preserving or even rejuvenating endothelial function offers a potent means of preventing/treating some of the most fearful aspects of aging such as loss of mental, cardiovascular, and sexual function.

Endothelial precursor cells (EPC) provide a continual source of replenishment of damaged or senescent blood vessels. The nutritional supplement Stem Kine contains ellagic acid and polyphenol antioxidant found in numerous vegetables and fruits; vitamin D3 which has been shown to mildly increase circulating progenitor cells; beta 1,3 glucan, and ferment of the bacterium , lactobacillus fermentum.

Placental Mesenchymal and Cord Blood Stem Cell Therapy for Dilated Cardiomyopathy

Ichim T, Solano F, Brenes R, Glenn E, Chang J, Chan K, Riordan N. – Reproductive BioMedicine Online 2008; 898-905

Regenerative treatment od dilated,non ischemic cardiomyopathy represent a significan clinical unmet need. Intracardiac administration of autologous bone marrow stem cells has demonstrated positive results in treatment of post infarct and chronic ischemic patients. Limitations to this procedure includes: invasiveness of bone marrow extraction and cardiac catheterization, and dependence of owns patient stem cell population that might be aged and possible senescent. In this paper we discuss the use of intravenous administered allogenic placental matrix and derived mesenchymals stem cells for treatment of dilated cardiomyopathy. Safety of this population has already been reported.

Allogenic Endometrial Regenerative Cells: An “Off the Shelf” Solution for Critical Limb Ischemia

Murphy A, Wang H, Patel A, Kambhampati S, Angle N, Chan K, Marleau A, Pyszniak A, Carrier E, Ichim T, Riordan N. – Journal of Traslational medicine. 2008; 6:45

Critical limb ischemia is an advance form of peripheral artery disease. 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.

The endometrial regenerative cells are a mesenchymal like stem cell derived from menstrual blood that is believed to be associated with endometrial angiogenesis. We discuss the possibility of using allogenic ERC’s as an off the shelf treatment for CLI based on the following properties: high levels of growth factors and matrix metalloproteasa production, ability to inhibits inflammatory responses and lack of immunogenicity and expandability to great quantities without loss of differentiation ability or karyotypic abnormalities.

Antigen Specific Therapy of Rheumatoid Arthritis

Ichim T. Zheng X, Suzuki M, Kubo N, Zhang X, Min L, Beduhn M, Riordan N, Inman R, Min W. – Expert opin. Biol. Ther. 2008; 8(2): 191-199

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 mechanism of auto reactivity, as well as clinically implementing immune based therapies that are antigen nonspecific.

Stem Cell Therapy for Autism

Ichim T, Solano F, Glenn E, Morales F, Smith L, Zabrecky G, Riordan N. – Journal of Translational Medicine 2007, 5:30

Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions whose incidence is reaching epidemic proportions, afflicting approximately in 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 lack of neural blood flow appear to be broadly consistent. These appear to be causative since correlation of altered inflammatory responses, and low blood flow with symptomatology is reported. Mesenchymal stem cells (MSC) are used for treating immune dysregulation (autoimmune conditions). Cord blood CD34+ cells are known to be potent angiogenic stimulators (new blood vessel growth), having demonstrated positive effects in different types of ischemia (restriction in blood supply). We propose that the combined use of MSC and cord blood CD 34+ cells may be useful in the treatment of autism.

Cord Blood in Regenerative Medicine: Do We Need Immune Suppression?

Riordan N, Chan K, Marleau A, Ichim T. – Journal of Translational Medicine 2007, 5:8

Cord blood is currently used as an alternative to bone marrow as a source of stem cells for hematopoietic reconstitution after destruction of the bone marrow own cells, and also a variety of indications ranging from stroke to limb ischemia, to myocardial regeneration. Due to unique immunological properties of both the stem cell and non stem cell components of cord blood, it may be possible to utilize allogenic cells for regenerative applications without needing to fully compromise the recipient immune system since they don’t are rejected by the recipient.

Endometrial Regenerative Cells – A Novel Stem Cell Population

Meng X, Ichim T, Zhong J, Rogers A, Yin Z, Jackson J, Wang H, Ge W, Bogin V, Chan K, Thebaud B, Riordan N – Journal of Translational Medicine 2007; 5:57

Angiogenesis (new blood vessels formation) 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. Endometrial regenerative cells (ERC) were capable of differentiating into nine lineages: cadiomyicitic, respiratory epithelial, neurocytic, myocytic, endothelial, pancreatic, hepatic, adipocytic and osteogenic. Given the ease of extraction and pluripotency of this cell population, we propose ERC as a novel alternative to current stem cell sources. This cell population may become a practical solution of choice for autologous stem cell therapy.