Stem Cell Science
Scientific Articles
1. 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
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2.
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. riordan@medisteminc.com
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
3. 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. jzhonguro@gmail.com
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
4. 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]
5. 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. mipmurph@iupui.edu
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]
6. 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]
7. 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]
8. 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,
mxl@brightspot.org
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]
9. 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.
thomas.ichim@gmail.com
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]
10. 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]
11. 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. nhriordan@gmail.com
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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