Intravenous Administration of Human Umbilical Cord Blood Cells in a Mouse Model of Amyotrophic Lateral Sclerosis: Distribution, Migration, and Differentiation

Abstract

Amyotrophic lateral sclerosis (ALS), a multifactorial disease characterized by diffuse motor neuron degeneration, has proven to be a difficult target for stem cell therapy. The primary aim of this study was to determine the long-term effects of intravenous mononuclear human umbilical cord blood cells on disease progression in a well-defined mouse model of ALS. In addition, we rigorously examined the distribution of transplanted cells inside and outside the central nervous system (CNS), migration of transplanted cells to degenerating areas in the brain and spinal cord, and their immunophenotype. Human umbilical cord blood (hUCB) cells (10(6)) were delivered intravenously into presymptomatic G93A mice. The major findings in our study were that cord blood transfusion into the systemic circulation of G93A mice delayed disease progression at least 2-3 weeks and increased lifespan of diseased mice. In addition, transplanted cells survived 10-12 weeks after infusion while they entered regions of motor neuron degeneration in the brain and spinal cord. There, the cells migrated into the parenchyma of the brain and spinal cord and expressed neural markers [Nestin, III Beta-Tubulin (TuJ1), and glial fibrillary acidic protein (GFAP)]. Infused cord blood cells were also widely distributed in peripheral organs, mainly the spleen. Transplanted cells also were recovered in the peripheral circulation, possibly providing an additional cell supply. Our results indicate that cord blood may have therapeutic potential in this noninvasive cell-based treatment of ALS by providing cell replacement and protection of motor neurons. Replacement of damaged neurons by progeny of cord blood stem cells is probably not the only mechanism by which hUCB exert their effect, since low numbers of cells expressed neural antigens. Most likely, cord blood efficacy is partially due to neuroprotection by modulation of the autoimmune process.

Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model

“…(e) Tail suspension test-The mouse was suspended by its tail and extension of hindlimbs observed (Garbuzova-Davis et al, 2003). The deficits scores are: grade 0, normal; grade 1, partial hindlimb extension; grade 2, no hindlimb extension.…”

Intravascular cell replacement therapy for stroke

“…In animal models with a neuroinflammatory component such as stroke, traumatic brain injury, spinal cord injury, and multiple sclerosis, therapeutic somatic stem cells (for example, BMSCs, umbilical cord blood stem cells, MSCs, and NPCs) target inflamed CNS areas where they persist for months and promote recovery through neuroprotective mechanisms. 17,27,56,90,98 It is thought that the process of transendothelial migration of somatic stem cells may be regulated in a manner similar to that of inflammatory cells. As early as 30 minutes after stroke, the infiltration of leukocytes, both polymorphonuclear leukocytes and monocytes/macrophages, can be observed.…”

Point-Of-Care Stem Cell Therapy (POCST): Multisite transplantation of autologous bone marrow-derived mononuclear cells in 85 patients with Amyotrophic Lateral Sclerosis improves survival

“…Neuroprotection probably occurs through the regulation of the immune system and the inflammatory response [30]. Later, several groups reproduced these findings, describing also paracrine mechanisms of immunomodulation occurring through secretomes, substances that are released when mononuclear cells die [31][32][33]. This change of paradigm is modifying our understanding of regenerative therapies for neurological disease.…”

“…Previous publications described a neuroprotective and neuro regenerative effect of BM-MNCs in CNS [28][29][30] probably due to growth factors that regulate the immune system [31][32][33]. Besides, these BM-MNCs that include mesenchymal (MSCs) and hematopoietic stem cells (HSCs) have been specifically described in ALS models to regenerate motoneurons [41][42][43][44], replace astrocytes contributing to slow motoneuron loss [45], regenerate microglia [46,47] and secrete growth factors promoting maintenance of healthy motoneurons [48,449].…”