Current Stem Cell Research & Therapy - Volume 6, Issue 4, 2011

Mesenchymal stem cells (MSCs) were discovered as a rare population of non-hematopoietic stem cells that reside in the bone marrow and interact closely with hematopoietic stem cells to support their growth and differentiation. MSCs are multipotent cells that have the ability to differentiate into cells of the mesenchymal lineage including adipocytes, osteocytes and chondrocytes and they have been reported to home to areas of tissue injury and participate in tissue repair. More recently, MSCs have also been described to possess anti-inflammatory and immunomodulatory properties that can affect multiple arms of the immune system. MSCs have been shown to inhibit T and B cell proliferation, downregulate the lytic activity of cytotoxic T lymphocytes and NK cells, inhibit the maturation and antigen-presenting function of dendritic cells and modulate macrophage function through both contact-dependent and contact-independent mechanisms. The administration of MSCs in models of autoimmune disease such as collagen-induced arthritis, EAE and autoimmune diabetes has provided additional evidence for an immunoregulatory role of MSCs supporting their use in controlling autoimmunity. The administration of allogeneic MSCs as immunosuppressive agents represents a viable approach as they appear to be largely non-immunogenic and clinical trials with allogeneic MSCs are currently underway in graftversus- host disease, Crohn's disease and type I diabetes indications. The immunomodulatory properties, mechanism of action and potential clinical utility of MSCs are reviewed herein.

Degeneration of the intervertebral disc is an age-related progressive process considered to be the major cause of a series of spine disorders, such as low-back pain that affects the majority of adult population and causes a huge loss of time from work and medical expenses. Numerous regenerative approaches are being developed with the aim to halt or reverse degeneration, including intradiscal administration of nucleus pulposus cells and mesenchymal stem cells and anabolic growth factors. Each of the currently proposed approaches, however, has exhibited certain limitations or shortcomings, largely due to our limited understanding on the cell biology, turnover mechanisms of the intervertebral disc as well as the etiology of disc degeneration. Intervertebral disc, particularly the central nucleus pulposus, is the largest enclosed and avascular tissue in the body and owes a microenvironment under high mechanical and osmotic pressures, at severely hypoxia, and with very limited nutrient supply. In order to achieve an optimal outcome of new regenerative therapies in such a harsh circumstance, identifying and characterizing endogenous regenerative properties of normal and degenerate intervertebral disc, including stem/progenitor cells themselves and extracellular factors located within the stem cell niche, may provide effective insights into selecting the most suitable cell sources and improving or rebuilding the microenvironment favorable for endogenous or transplanted stem cells.

The plasticity of neural stem/progenitor cells allows a variety of different responses to many environmental cues. In the past decade, significant research has gone into understanding the regulation of neural stem/progenitor cell properties, because of their promise for cell replacement therapies in adult neurological diseases. Both endogenous and grafted neural stem/progenitor cells are known to have the ability to migrate long distances to lesioned sites after brain injury and differentiate into new neurons. Several chemokines and growth factors, including stromal cell-derived factor-1 and vascular endothelial growth factor, have been shown to stimulate the proliferation, differentiation, and migration of neural stem/progenitor cells, and investigators have now begun to identify the critical downstream effectors and signaling mechanisms that regulate these processes. Both our own lab and others have shown that the extracellular matrix and matrix remodeling factors play a critical role in directing cell differentiation and migration of adult neural stem/progenitor cells within injured sites. Identification of these and other molecular pathways involved in stem cell homing into ischemic areas is vital for the development of new treatments. To ensure the best functional recovery, regenerative therapy may require the application of a combination approach that includes cell replacement, trophic support, and neural protection. Here we review the current state of our knowledge about endogenous adult and exogenous neural stem/progenitor cells as potential therapeutic agents for central nervous system injuries.

The concept that the genesis of new cells in the adult mammalian brain is negligible has long influenced our perception and understanding of the origin and development of central nervous system (CNS) tumors. The discovery that neurons and glia are produced throughout life from neural stem cells provides new possibilities for candidate precursor cells of CNS neoplasms. The emerging hypothesis is that alterations in the cellular and genetic mechanisms that control adult neurogenesis might contribute to brain tumorigenesis. As such, opportunities become available to identify new therapeutic strategies.

Retinal degenerations are the leading cause of genetically inherited blindness. One of the strategies currently being tested for the treatment is cell/tissue transplantation. As such stem cells and tissue engineered constructs are of great importance. This report describes the growth of multipotential human retinal progenitors (cell line) in a 3-D bioreactor culture vessel with (adhesive substrate) laminin coated collagen 1/cytodex beads and without adhesive substrate (beadless culture). The study demonstrates that progenitors are capable of growth and differentiation in the bioreactor with or without beads. The presence of adhesive substrate accelerates and enhances photoreceptor differentiation in the bioreactor, reflected by significantly higher level expressions of several photoreceptor specific proteins; N acetyl transferase (AaNat), rhodopsin and cone transducin GNB3. Both monomeric and dimeric forms of rhodopsin are expressed in cells attached to beads, whereas, only the monomeric form is expressed in beadless culture. Similarly, a different isomeric form of tyrosine hydroxylase (a doublet) is expressed in cell bead attached cultures. Co-culturing retinal progenitors with retinal pigment epithelium (RPE) in cell bead cultures further stabilizes the photoreceptor phenotype and rhodopsin expression. Most of the retinal neuronal phenotypes are confirmed by an expression of specific proteins. The adhesive substrate in the form of collagen 1, laminin coated cytodex beads, could be just an effector for stabilization or a positive signal, modulating extracellular matrix (ECM) molecules and/or neurotrophins. In the future, the bioreactor culture system could be utilized to grow retina-like structures from ciliary epithelium by incorporating biodegradable substrates.

Background: Acute renal failure (ARF) resulting from ischemic or toxic insults remains a major health care problem because of its grave prognosis and the limited effectiveness of available treatment modalities. Current treatment options for ARF are limited to supportive measures and preventive strategies, none of which have been definitively shown to alter mortality. Aim: To assess the ability of human umbilical cord blood CD34+ (HUCB CD34+) cells and mononuclear (HUCB MNC) cells to improve renal function of nephrotoxic kidney. Methods: ARF was induced in 30 rats by glycerol. After 24 hours, ARF was confirmed by increased blood urea nitrogen (BUN), serum urea and creatinine levels. The rats were divided into 3 groups, group one included 10 rats treated with HUCB CD34+ cells, group two included 10 rats treated with HUCB MNC and group three included 10 rats treated with normal saline. Five rats were included in the study as a normal control group. Serial measurement of BUN, serum urea and creatinine levels were done every three days throughout the study. To proof homing of HUCB CD34+ into renal tissue, Y chromosome detection in renal tissue was carried out using Real time polymerase chain reaction (PCR) technique. Results: Four days after the therapy, the renal function of CD34+ and MNC treated rats improved in comparison to saline treated rats. After 2 weeks of therapy and at the end of the study (28 days), ANOVA test revealed that, there was significant difference between the four studied groups (P=.000). Y chromosomes were detected in kidneys of CD34+ treated rats and MNC treated rats. Conclusion: HUCB CD34+ cells and HUCB MNC improve renal function of nephrotoxic kidney with superiority to the HUCB MNC.

Mesenchymal stem cells (MSCs) hold great promise as therapeutic agents in regenerative medicine. Numerous animal studies have documented the multipotency of MSCs, showing their capabilities for differentiating into orthopedic tissues such as muscle, bone, cartilage, and tendon. However, the safety of culture expanded MSC's for human use has only just begun to be reported. Methods: Between 2006 and 2010, two groups of patients were treated for various orthopedic conditions with cultureexpanded, autologous, bone marrow-derived MSCs (group 1: n=50; group 2: n=290-one patient in both groups). Cells were cultured in monolayer culture flasks using an autologous platelet lysate technique and re-injected into peripheral joints or into intervertebral discs with use of c-arm fluoroscopy. While both groups had prospective surveillance for complications, Group 1 additionally underwent 3.0T MRI tracking of the re-implant sites. Results: The mean age of patients treated was 53 +/- 13.85 years; 214 were males and 125 females with mean follow-up time from any procedure being 435 days +/- 261 days. Number of contacts initiated based on time from first procedure was 482 at 3 months, 433 at 6 months, 316 contacts at 12 months, 110 contacts at 24 months, and 22 contacts at 36 months. For Group 1, 50 patients underwent 210 MRI surveillance procedures at 3 months, 6 months, 1, 2, and 3 years which failed to demonstrate any tumor formation at the re-implant sites. Formal disease surveillance for adverse events based on HHS criteria documented significantly less morbidity than is commonly reported for more invasive surgical procedures, all of which were either self-limited or were remedied with therapeutic measures. Two patients were diagnosed with cancer out of 339 patients treated since study inception; however, this was almost certainly unrelated to the MSC therapy and the neoplasm rate in similar to that seen in the U.S. Caucasian population. Knee outcome data was collected on a subset of patients. Here, >75% improvement was reported in 41.4% while decreasing the improvement threshold to >50% improvement, 63.2% reported an improvement. At an average reporting time of 11.3 months from first procedure average reported relief in the knee sample equaled 53.1% (n=133 reporting). Conclusions: Using both intensive high field MRI tracking and complications surveillance in 339 patients, no neoplastic complications were detected at any stem cell re-implantation site. These findings are consistent with our prior publication and other published reports that also show no evidence of malignant transformation in vivo, following implantation of MSCs for orthopedic use.