Investigating nanoparticle's utilization in stem cell therapy for neurological disorders.

Human stromal (mesenchymal) stem cells (hMSC) represent a group of non-hematopoietic stem cells present in the bone marrow stroma and the stroma of other organs including subcutaneous adipose tissue, placenta, and muscles. They exhibit the characteristics of somatic stem cells of self-renewal and multi-lineage differentiation into mesoderm-type of cells, e.g., to osteoblasts, adipocytes, chondrocytes and possibly other cell types including hepatocytes and astrocytes. Due to their ease of culture and multipotentiality, hMSC are increasingly employed as a source for cells suitable for a number of clinical applications, e.g., non-healing bone fractures and defects and also non-skeletal degenerative diseases like heart failure. Currently, the numbers of clinical trials that employ MSC are increasing. However, several biological and biotechnological challenges need to be overcome to benefit from the full potential of hMSC. In this current review, we present some of the most important and recent advances in understanding of the biology of hMSC and their current and potential use in therapy.

Recent studies indicate that cardiac transfer of adult stem cells can have a favorable impact on tissue perfusion and contractile performance of the infarcted heart. Several cell sources are being explored in an effort to regenerate infarcted myocardium, including hematopoietic stem cells, endothelial progenitor cells, cardiac resident stem cells, bone marrow–derived multipotent stem cells, and mesenchymal stem cells (MSCs). Each of these cell types may have its own profile of advantages, limitations, and practicability issues in specific settings. Studies comparing the regenerative capacity of distinct cell populations are scarce. Most clinical investigators have therefore chosen a pragmatic approach by using unselected bone marrow cells that contain different stem cell populations. Basic scientists, by contrast, are focusing more on specific cell populations in a quest to understand the biological foundations of cell therapy and to identify the most promising stem cells for cardiac regeneration.1 See p 214 MSCs are a rare population of self-renewing, multipotent cells present in adult bone marrow. Although MSCs represent <0.01% of all nucleated bone marrow cells, they can be readily expanded in vitro. In defined culture media, MSCs differentiate into several mesenchymal cell lineages, including cardiomyocytes.2,3 When injected into normal adult myocardium, MSCs differentiate into cardiomyocyte-like cells with sarcomeric organization.4 In an earlier study in pigs with myocardial infarction (MI), MSCs grafted into the infarcted area were shown to express muscle-specific markers and to improve regional wall motion.5 Ease of isolation, high expansion capability, and cardiomyogenic potential have led to the proposition that MSCs may be a good choice for cell-based therapies of MI.6 In a report published in this issue of Circulation , Dai et al7 have …

What's in a Name?

The Promise and Perils of Stem Cell Therapeutics

recent Nobel Prize in medicine was awarded to two stemcell researchers, John Gurdon and Shinya Yamanaka, for theirachievements in stem cell research and reprogramming ofsomatic cells. Flow cytometry is by nature the ideal tool toidentify, characterize, and isolate stem and progenitor cells forresearch and potential clinical use (1). The major strength offlow cytometry is its ability to rapidly perform highlymultiplexed quantitative measurements on single cells withina heterogeneous cell population. However, when the cell typeof interest is extremely rare, as most stem and progenitor cellsare, several sources of artifact must be addressed. The impor-tance of flow cytometry as a driving force for stem cellresearch was demonstrated in a focused issue of the journalexactly three years ago (1). This current focus issue of Cytome-try A is devoted to the topic of stem cells due to numerouscurrent innovations and discoveries.Applications of stem cells include several disciplines,from embryogenesis, adult tissue maintenance, and repair,and more recently, cancer as well as for toxicity screening anddisease modeling. All of these topics are represented in thisissue, with special emphasis on the role of analytic and pre-parative flow cytometry in the elucidation of stem cell pheno-type and function, and best laboratory practices as they applyto flow cytometry. Image and flow cytometry together withcell sorting have revolutionized the study of stem cell biologyand the implications of these cells and their progeny indevelopmental biology, tissue engineering, and cellulartherapy. The number of parameters and the speed of theirsimultaneous measurements in single cells has continued toincrease with advances in hardware, reagents, and analyticalsoftware (2).

913 WE WRITE TO COMMENT BRIEFLY on the neurological literature on blood-derived neural stem cells, and to offer a case report regarding the safety of a simple procedure to introduce stem cells to the cerebrospinal fluid (CSF) compartment. For decades there has been evidence for cells of common neural and hematopoietic potential; this phenomenon was originally demonstrated by the presence of pluripotent cells resident in the adult brain that could form hematopoietic colonies in irradiated animals, as well as antigenic cross-reactivity between certain neural and hematopoietic cells (1–3). Recent studies have reproduced and confirmed the pleuripotency of neuro-hematopoietic cells, and showed that “blood can turn into brain” and vice-versa (4–6). Dr. W. Krivit at Harvard was the first to show that bone marrow transplantation (BMT) ameliorates some forms of central nervous system (CNS) genetic and metabolic disease (7), thought to be due to cellular margination and passage of the blood–brain barrier, which raised the intriguing idea of grafting blood cells directly to the human CNS. Indeed, administration of bone marrow-derived cells to the brain with neuronal engraftment has been demonstrated in animal models (8), and published reports now show blood stem cell differentiation along various neural lineages, including neurons and astrocytes. In an important clinical experiment conducted in Sweden, a group of patients received an intravenous (i.v.) label of bromodeoxyuridine (BrdU), which detects division of new cells. This work proved that neural progenitor cells exist in the brain of the adult human (9), thus generalizing an observation from primates and other animals that had generated much controversy, because it challenged a long-held tenet that brain cells could not be replenished or regenerate in situ. The precise source of neural progenitor cells is still a matter of debate and speculation, but the consensus is that they appear to be enriched around vascular tissues in the forebrain subventricular zone, the ependyma, and the dentate gyrus of the hippocampus. Given the close association between the vasculature and the sources of neural stem cells (10), one possibility is that neural stem cells arise in the adult human brain both from primordial brain stem cells and from migratory hematopoietic-derived cells. Considering the lack of effective drugs for amyotrophic lateral sclerosis (ALS) and accumulating evidence that primordial blood-derived cells can adopt a neuronal or glial fate, in 1999 we began exploring a blood stem cell selection protocol for application to ALS, in parallel with long-term plans for other experimental approaches. The objective was to bring to the clinic any promising drug or treatment protocol that had already been approved for human use. CD341 stem cell selection protocols are widely used in bone marrow transplants and are approved by the U.S. Food and Drug Administration (FDA), although clinical application for ALS is “off-label.” Immune ablation followed by BMT has already been performed in studies on multiple sclerosis and other primary CNS conditions; however, the mechanism we anticipated is one of cell grafting, CNS-specific differentiation, and local trophic effects, rather than the reconstitution of pharmacologically depleted immune cells. To demonstrate safety and generate preliminary data in support of dosing and method of deliver, we transplanted adult human marrow and fetal CD341 cells directly into the nonimmunosuppressed monkey spinal cord and intrathecal space. The monkeys underwent laminectomies, and xenogeneic human cells were introduced to the midline of the dorsal spinal cord at multiple sites using a Hamilton syringe and 30-gauge needle, without adverse behavioral or serological responses. The limited work available in the literature on cord blood transplants to superoxide dismutase (SOD1) mice also supported our ra-

CORR Synthesis: What Is the Evidence for the Clinical Use of Stem Cell-based Therapy in the Treatment of Osteoarthritis of the Knee?

Stem Cell Biotech: Seeking a Piece of the Action

Global Challenges in Stem Cell Research and the Many Roads Ahead

Human neurological diseases such as Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), multiple sclerosis (MS), stroke and spinal cord injury are caused by a loss of neurons and glial cells in the brain or spinal cord. Cell replacement therapy and gene transfer to the diseased or injured brain have provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases. However, the paucity of suitable cell types for cell replacement therapy in patients suffering from neurological disorders has hampered the development of this promising therapeutic approach. In recent years, neurons and glial cells have successfully been generated from stem cells such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs) and neural stem cells (NSCs), and extensive efforts by investigators to develop stem cell-based brain transplantation therapies have been carried out. I review here notable experimental and pre-clinical studies previously published involving stem cell-based cell- and gene-therapies for PD, HD, ALS, AD, MS and stroke, and discuss for future prospect for the stem cell therapy of neurological disorders in clinical setting. There are still many obstacles to be overcome before clinical application of cell- and gene-therapy in neurological disease patients is adopted: (i) it is still uncertain how to generate specific cell types of neurons or glia suitable for cellular grafts in great quantity, (ii) it is required to abate safety concern related to tumor formation following NSC transplantation, and (iii) it needs to be better understood by what mechanism transplantation of NSCs leads to an enhanced functional recovery. Steady and stepwise progress in stem cell research in both basic and pre-clinical settings should support the hope for development of stem cell-based therapies for neurodegenerative diseases. This review focuses on the utility of stem cells particularly NSCs as substrates for structural and functional repair of the diseased or injured brain.

Cardiac stem cell therapy: Does a newborn infant's heart have infinite potential for stem cell therapy?

The objective of the research is to investigate the role of very small embryonic-like stem cells (VSELs™), as well as CD34 + cells, in a study that will compare the efficacy of these two cell types for retinal repair.Licensing agreement: TiGenix & Sobi TiGenix (Belgium; www.tigenix.com)has licensed the marketing and distribution of ChondroCelect ® , the cell-based medicinal product for the repair of cartilage defects of the knee, to the international specialty healthcare company dedicated to rare diseases, Swedish Orphan Biovitrum AB (www.sobi.com).ChondroCelect was the first cellbased product to be approved in Europe.It is currently available for patients and reimbursed in Belgium, The Netherlands and Spain.Sales of ChondroCelect in 2013 were US$5.76 (EU€4.3)million, a growth of 25% on a like-for-like basis over 2012.Sobi will continue to market and distribute the product where it is currently available and has also acquired the exclusive rights to expand the product's availability to patients in multiple additional territories, including the rest of the EU, Norway, Switzerland, Turkey and Russia, plus the countries of the Middle East and North Africa.TiGenix will receive a royalty of 22% of the net sales of ChondroCelect in the first year of the agreement, and 20% of the net sales of ChondroCelect thereafter.There will be no upfront or milestone payments.The agreement took effect on June 1, 2014, and has a duration of 10 years. Launching new projects, products & servicesCatapult

Translating Stem Cell Studies to the Clinic for CNS Repair: Current State of the Art and the Need for a Rosetta Stone

SummaryThe gap in knowledge of the molecular mechanisms underlying differentiation of human pluripotent stem cells (hPSCs) into the mesenchymal cell lineages hinders the application of hPSCs for cell-based therapy. In this study, we identified a critical role of muscle segment homeobox 2 (MSX2) in initiating and accelerating the molecular program that leads to mesenchymal stem/stromal cell (MSC) differentiation from hPSCs. Genetic deletion of MSX2 impairs hPSC differentiation into MSCs. When aided with a cocktail of soluble molecules, MSX2 ectopic expression induces hPSCs to form nearly homogeneous and fully functional MSCs. Mechanistically, MSX2 induces hPSCs to form neural crest cells, an intermediate cell stage preceding MSCs, and further differentiation by regulating TWIST1 and PRAME. Furthermore, we found that MSX2 is also required for hPSC differentiation into MSCs through mesendoderm and trophoblast. Our findings provide novel mechanistic insights into lineage specification of hPSCs to MSCs and effective strategies for applications of stem cells for regenerative medicine.

Too Much Carrot and Not Enough Stick in New Stem Cell Oversight Trends.