Mesenchymal stem cells as cellular vectors for pediatric neurological disorders

Abstract

Lysosomal storage diseases are a heterogeneous group of hereditary disorders characterized by a deficiency in lysosomal function. Although these disorders differ in their etiology and phenotype those that affect the nervous system generally manifest as a profound deterioration in neurologic function with age. Over the past several decades implementation of various treatment regimens including bone marrow and cord blood cell transplantation, enzyme replacement, and substrate reduction therapy have proved effective for managing some clinical manifestations of these diseases but their ability to ameliorate neurologic complications remains unclear. Consequently, there exists a need to develop alternative therapies that more effectively target the central nervous system. Recently, direct intracranial transplantation of tissue-specific stem and progenitor cells has been explored as a means to reconstitute metabolic deficiencies in the CNS. In this chapter we discuss the merits of bone marrow-derived mesenchymal stem cells (MSCs) for this purpose. Originally identified as progenitors of connective tissue cell lineages, recent findings have revealed several novel aspects of MSC biology that make them attractive as therapeutic agents in the CNS. We relate these advances in MSC biology to their utility as cellular vectors for treating neurologic sequelae associated with pediatric neurologic disorders.

MicroRNAs in Control of Stem Cells in Normal and Malignant Hematopoiesis

“…For example, exosomes from mesenchymal stromal cells contain a number of miRNAs, including miR-451, miR-1202, miR-630, miR1207-5p, miR-33b, miR-1268, miR-638, miR-575, and miR-1225-5p [130]. Whether exosomal miRNAs from bone marrow stromal cells regulate hematopoiesis in vivo is currently unknown.…”

Mesenchymal Stem Cells Yield Transient Improvements in Motor Function in an Infant Rhesus Macaque with Severe Early-Onset Krabbe Disease

“…Mesenchymal stem cells (MSCs), a type of adult stem cell initially identified in bone marrow, are known to possess potent angiogenic, anti‐inflammatory, and immunomodulatory activities that are largely paracrine in nature and are being evaluated in human clinical trials to treat a diverse array of non–skeletal‐related diseases. Consistent with these findings, MSC‐based therapies have yielded benefits in rodent models of storage diseases by restoring deficient enzyme levels, reducing inflammation, and promoting survival of neural cell types . We previously demonstrated that MSCs administered via the intracranial route into healthy infant rhesus macaques exhibited low levels of durable cell engraftment and distributed nonrandomly along the brain neuraxis throughout both brain hemispheres, without producing adverse effects on the health or social, behavioral, cognitive, or motor abilities of animals up to 6 months post‐transplant .…”

“…Mesenchymal stem cells (MSCs), a type of adult stem cell initially identified in bone marrow, are known to possess potent angiogenic, anti-inflammatory, and immunomodulatory activities that are largely paracrine in nature [18][19][20][21][22] and are being evaluated in human clinical trials to treat a diverse array of non-skeletalrelated diseases. Consistent with these findings, MSC-based therapies have yielded benefits in rodent models of storage diseases by restoring deficient enzyme levels, reducing inflammation, and promoting survival of neural cell types [23].…”

Novel clinical uses for cord blood derived mesenchymal stromal cells

“…There are suggestions that MSCs support wound healing and tissue regeneration through vessel forming and inhibition of apoptosis. More clinical trials are underway and are needed to evaluate the safety, feasibility and efficacy of CB/CT-derived MSCs as a delivery mechanism for cellular therapy in a variety of applications-for example, malignancies [64]; neurologic disorders [65,66]; primary biliary and decompensated cirrhosis; myocardial and neuronal ischemia; bone disease; connective tissue, skin and cartilage repair; and in autoimmune diseases such as lupus and rheumatoid arthritis. An improved understanding of the biology of CB/CT-derived MSCs in vivo may allow further broadening of applications.…”