Preclinical Studies with Umbilical Cord Mesenchymal Stromal Cells in Different Animal Models for Muscular Dystrophy

Abstract

Umbilical cord mesenchymal stromal cells (MSC) have been widely investigated for cell-based therapy studies as an alternative source to bone marrow transplantation. Umbilical cord tissue is a rich source of MSCs with potential to derivate at least muscle, cartilage, fat, and bone cells in vitro. The possibility to replace the defective muscle cells using cell therapy is a promising approach for the treatment of progressive muscular dystrophies (PMDs), independently of the specific gene mutation. Therefore, preclinical studies in different models of muscular dystrophies are of utmost importance. The main objective of the present study is to evaluate if umbilical cord MSCs have the potential to reach and differentiate into muscle cells in vivo in two animal models of PMDs. In order to address this question we injected (1) human umbilical cord tissue (hUCT) MSCs into the caudal vein of SJL mice; (2) hUCT and canine umbilical cord vein (cUCV) MSCs intra-arterially in GRMD dogs. Our results here reported support the safety of the procedure and indicate that the injected cells could engraft in the host muscle in both animal models but could not differentiate into muscle cells. These observations may provide important information aiming future therapy for muscular dystrophies.

Concise Review: Mesoangioblast and Mesenchymal Stem Cell Therapy for Muscular Dystrophy: Progress, Challenges, and Future Directions

“…Functional benefit was observed in both SJL/J and Lama2 dy-2J mice. Despite this, neither human nor canine ucMSCs expressed muscle proteins [38][39][40][41], indicating that ucMSCs lack myogenic potential in vivo in animal models for muscular dystrophy. However, forced expression of MyoD in ucMSCs enhanced skeletal muscle differentiation in vitro [42] and might also be useful to stimulate their myogenic differentiation in vivo, because this approach has been used to improve skeletal muscle differentiation of MSCs from synovium and orthopedic surgery remnants in vitro and in vivo [43,44].…”

“…Human ucMSCs were transplanted systemically into Swiss Jim Lambert (SJL/J) mice [38,39] (a murine model for LGMD containing a mutation in the dysferlin gene), the laminin a2 dystrophia muscularis 2 Jackson (Lama2 dy-2J ) mice [40] (a murine model for congenital muscular dystrophy), and Golden Retriever muscular dystrophy (GRMD) dogs [39,41] (a canine model for DMD with a naturally occurring mutation in the gene encoding dystrophin). In addition, canine ucMSCs were isolated and transplanted into dog leukocyte antigen-histocompatible GRMD littermates [39].…”

“…In addition, canine ucMSCs were isolated and transplanted into dog leukocyte antigen-histocompatible GRMD littermates [39]. In all three studies, ucMSCs infiltrated dystrophic muscle from the circulation, detected by polymerase chain reaction for human DNA, immunohistochemistry for human antigens, or the presence of Y chromosome-specific sequences in recipient females.…”

Relevant aspects of golden retriever muscular dystrophy for the study of Duchenne muscular dystrophy in humans

“…However, the expression of dystrophin was not detected in the animals after transplantation. Results showed that umbilical cord mesenchymal stem cells could be able to reach the animal's musculature, but would not be able to reach full differentiation in skeletal muscle cells (ZUCCONI et al, 2011). More recently, it has been reported that adipose cells derived from human stroma, when injected systemically into the dog's cephalic vein, could have the ability to penetrate, implant and express the dystrophin in the dystrophic muscle of the DGR up to 6 months after transplantation.…”

<b>Avaliação sequencial do metabolismo de cálcio e fósforo com ênfase na determinação do fator de crescimento de fibroblastos 23 (FGF-23) e da excreção fracionada de fósforo urinária (uFEP) de cães com doença renal crônica submetidos a terapia com células-tronco mesenquimal</b>

“…Com o recente progresso na pesquisa sobre o tratamento com as células-tronco, têm-se discutido sobre a possibilidade de regeneração tecidual ou, principalmente, da sua ação em minimizar os mecanismos de auto-perpetuação da lesão renal, tanto inflamatórios quanto imunológicos CAO et al, 2010;LIM et al, 2011;VIEIRA et al, 2011;ZUCCONI et al, 2011), sinalizando como uma nova ferramenta na terapia da DRC em cães (LIM et al, 2016 (GEDDES et al, 2013a;FOSTER, 2016;SEGEV;MELTZER;SHIPOV, 2016).…”