https://journals.sagepub.com/doi/pdf/10.3727/096368915X689622

Clinical Trials with Mesenchymal Stem Cells: An Update:

Stem cells are cells specialized cell, capable of renewing themselves through cell division and can differentiate into multi-lineage cells. These cells are categorized as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adult stem cells. Mesenchymal stem cells (MSCs) are adult stem cells which can be isolated from human and animal sources. Human MSCs (hMSCs) are the non-haematopoietic, multipotent stem cells with the capacity to differentiate into mesodermal lineage such as osteocytes, adipocytes and chondrocytes as well ectodermal (neurocytes) and endodermal lineages (hepatocytes). MSCs express cell surface markers like cluster of differentiation (CD)29, CD44, CD73, CD90, CD105 and lack the expression of CD14, CD34, CD45 and HLA (human leucocyte antigen)-DR. hMSCs for the first time were reported in the bone marrow and till now they have been isolated from various tissues, including adipose tissue, amniotic fluid, endometrium, dental tissues, umbilical cord and Wharton's jelly which harbours potential MSCs. hMSCs have been cultured long-term in specific media without any severe abnormalities. Furthermore, MSCs have immunomodulatory features, secrete cytokines and immune-receptors which regulate the microenvironment in the host tissue. Multilineage potential, immunomodulation and secretion of anti-inflammatory molecules makes MSCs an effective tool in the treatment of chronic diseases. In the present review, we have highlighted recent research findings in the area of hMSCs sources, expression of cell surface markers, long-term in vitro culturing, in vitro differentiation potential, immunomodulatory features, its homing capacity, banking and cryopreservation, its application in the treatment of chronic diseases and its use in clinical trials.

Human mesenchymal stem cells - current trends and future prospective

Mesenchymal stem cells (MSCs) are multipotent cells that are being clinically explored as a new therapeutic for treating a variety of immune-mediated diseases. First heralded as a regenerative therapy for skeletal tissue repair, MSCs have recently been shown to modulate endogenous tissue and immune cells. Preclinical studies of the mechanism of action suggest that the therapeutic effects afforded by MSC transplantation are short-lived and related to dynamic, paracrine interactions between MSCs and host cells. Therefore, representations of MSCs as drug-loaded particles may allow for pharmacokinetic models to predict the therapeutic activity of MSC transplants as a function of drug delivery mode. By integrating principles of MSC biology, therapy, and engineering, the field is armed to usher in the next generation of stem cell therapeutics.

/pdf/mesenchymal-stem-cells-as-therapeutics-3n5jdxv64f.pdf

Mesenchymal Stem Cells as Therapeutics

Mesenchymal Stem Cells (MSCs) are non-hematopoietic multi-potent stem-like cells that are capable of differentiating into both mesenchymal and non-mesenchymal lineages. In fact, in addition to bone, cartilage, fat, and myoblasts, it has been demonstrated that MSCs are capable of differentiating into neurons and astrocytes in vitro and in vivo. MSCs are of interest because they are isolated from a small aspirate of bone marrow and can be easily expanded in vitro. As such, these cells are currently being tested for their potential use in cell and gene therapy for a number of human diseases. Nevertheless, there are still some open questions about origin, multipotentiality, and anatomical localization of MSCs. In this review, we discuss clinical trials based on the use of MSCs in cardiovascular diseases, such as treatment of acute myocardial infarction, endstage ischemic heart disease, or prevention of vascular restenosis through stem cell-mediated injury repair. We analyze data from clinical trials for treatment of osteogenesis imperfecta (OI), which is a genetic disease characterized by production of defective type I collagen. We describe progress for neurological disease treatment with MSC transplants. We discuss data on amyotrophic lateral sclerosis (ALS) and on lysosomal storage diseases (Hurler syndrome and metachromatic leukodystrophy). A section of review is dedicated to ongoing clinical trials, involving MSCs in treatment of steroid refractory Graft Versus Host Disease (GVHD); periodontitis, which is a chronic disease affecting periodontium and causing destruction of attachment apparatus, heart failure, and bone fractures. Finally, we will provide information about biotech companies developing MSC therapy.

/pdf/from-the-laboratory-bench-to-the-patient-s-bedside-an-update-1f54m0xiwc.pdf

From the laboratory bench to the patient's bedside: an update on clinical trials with mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are multipotent cells defined by multilineage potential, ease to gene modification, and immunosuppressive ability, thus holding promise for tissue engineering, gene therapy, and immunotherapy. They exhibit a unique in vitro expansion capacity, which, however, does not compensate for the very low percentage in their niches given the vast numbers of cells required for the relative studies. Taking into consideration the lack of a uniform approach for MSC isolation and expansion, we attempted in this study, by comparing various culture conditions, to identify the optimal protocol for the large-scale production of MSCs while maintaining their multilineage and immunosuppressive capacities. Our data indicate that, apart from the quality of fetal calf serum, other culture parameters, including basal medium, glucose concentration, stable glutamine, bone marrow mononuclear cell plating density, MSC passaging density, and plastic surface quality, affect the final outcome. Furthermore, the use of basic fibroblast growth factor (bFGF), the most common growth supplement in MSC culture media, greatly increases the proliferation rate but also upregulates HLA-class I and induces low HLA-DR expression. However, not only does this upregulation not elicit significant in vitro allogeneic T cell responses, but also bFGF-cultured MSCs exhibit enhanced in vivo immunosuppressive potential. Besides, addition of bFGF affects MSC multilineage differentiation capacity, favoring differentiation toward the osteogenic lineage and limiting neurogenic potential. In conclusion, in this report we define the optimal culture conditions for the successful isolation and expansion of human MSCs in high numbers for subsequent cellular therapeutic approaches.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1634/stemcells.2004-0331

Characterization of the optimal culture conditions for clinical scale production of human mesenchymal stem cells.

INTRODUCTION: Recently it has been shown in animal models of amyotrophic lateral sclerosis (ALS) that stem cells significantly slow the progression of the disease and prolong survival. We have evaluated the feasibility and safety of a method of intraspinal cord implantation of autologous mesenchymal stem cells (MSCs) in a few well‐monitored patients with ALS.METHOD: Bone marrow collection was performed according to the standard procedure by aspiration from the posterior iliac crest. Ex vivo expansion of mesenchymal stem cells was induced according to Pittenger's protocol. The cells were suspended in 2 ml of autologous cerebrospinal fluid and transplanted into the spinal cord by a micrometric pump injector.RESULTS: No patient manifested major adverse events such as respiratory failure or death. Minor adverse events were intercostal pain irradiation (4 patients) which was reversible after a mean period of three days after surgery, and leg sensory dysesthesia (5 patients) which was reversible after a mean pe...

Stem cell therapy in amyotrophic lateral sclerosis: a methodological approach in humans

https://www.archives-pmr.org/article/S0003-9993(03)00314-9/pdf

Posttraumatic hydrocephalus: a clinical, neuroradiologic, and neuropsychologic assessment of long-term outcome.

Summary: Purpose: We sought to detect the incidence and the risk factors of posttraumatic epilepsy (PTE) in rehabilitation patients; to define the influence of PTE for late clinical and functional outcome; and to assess the cognitive and behavioral features of the patients with PTE.



Methods: Patients were examined with (a) cognitive and behavioral examinations, which included a clinical interview and psychometric tests performed by an expert clinical psychologist; (b) single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI); and (c) functional evaluation including the Glasgow Outcome Scale (GOS) and the Functional Independence Measure (FIM).



Results: Of the 143 patients examined in this study, in 27 (19%), seizures developed after a mean time from trauma of 11.9 ± 8.6 months. The occurrence of PTE was significantly correlated with the hypoperfusion in temporal lobes (p < 0.004), the degree of hydrocephalus (p < 0.04), the evidence of intracerebral hematoma (p < 0.01), and operative brain injury (p < 0.001). Patients with epilepsy showed a significantly higher incidence of personality disorders than did patients without epilepsy. The disinhibited behavior, irritability, and agitated and aggressive behavior were significantly more frequent and severe in PTE patients. The psychometric tests intended to explore memory, language, intelligence, attention, and spatial cognition did not show any significant difference between those with and without epilepsy. PTE also was significantly correlated with a worse functional outcome 1 year after the trauma.



Conclusions: The degrees of hydrocephalus and of hypoperfusion in the temporal lobes are significant risk factors for late PTE. Another main finding of our study is the absence of influence of epilepsy on cognitive disorders; its influence on neurobehavioral disorders and functional outcome is discussed.

Posttraumatic Epilepsy: Neuroradiologic and Neuropsychological Assessment of Long‐term Outcome

The aim of this study was to translate the structured
assessment of depression in brain–damaged individuals
(SADBD) questionnaire into the Italian language, validate,
and test reliability and validity of the Italian version.
Consecutive patients with stroke were screened in the
Department of Neurology, Avogadro University in Novara
and the Department of Neurorehabilitation, Maugeri
Foundation, Veruno, Italy. Thirty patients were included in
the study. The internal consistency ranged between 0.78 and
0.87. The intra–rater test–retest reliability was 0.93 for BDIderived
items and 0.82 for HRSD–derived items; while the
inter–rater test–retest reliability was 0.94 for BDI–derived
items and 0.93 for HRSD–derived items. Correlation
between the SADBD diagnosis made by the physician and
the nurse was 0.51; correlation between caregiver and physician
diagnosis was 0.60. The Italian version of the SADBD
was demonstrated to be acceptable, reliable and a valid measure
of depression in patients with stroke.

Ilaria Pastore

Papers

Stem cell therapy in amyotrophic lateral sclerosis: a methodological approach in humans

Posttraumatic hydrocephalus: a clinical, neuroradiologic, and neuropsychologic assessment of long-term outcome.

Posttraumatic Epilepsy: Neuroradiologic and Neuropsychological Assessment of Long‐term Outcome

The structured assessment of depression in brain-damaged individuals: translation and validation study of the Italian version.