Modern day tissue engineering and cellular therapies have gravitated toward using stem cells with scaffolds as a dynamic modality to aid in differentiation and tissue regeneration. Mesenchymal stem cells (MSCs) are one of the most studied stem cells used in combination with scaffolds. These cells differentiate along the osteogenic lineage when seeded on hydroxyapatite containing scaffolds and can be used as a therapeutic option to regenerate various tissues. In recent years, the combination of hydroxyapatite and natural or synthetic polymers has been studied extensively. Due to the interest in these scaffolds, this review will cover the wide range of hydroxyapatite containing scaffolds used with MSCs for in vitro and in vivo experiments. Further, in order to maintain a progressive scope of the field this review article will only focus on literature utilizing adult human derived MSCs (hMSCs) published in the last three years.
Postnatal skeletal muscle development is a highly dynamic period associated with extensive transcriptome remodeling. A significant aspect of postnatal development is widespread alternative splicing changes, required for the adaptation of tissues to adult function. These splicing events have significant implications since the reversion of adult mRNA isoforms to fetal isoforms is observed in forms of muscular dystrophy. LIM and Calponin Homology Domains 1 (LIMCH1) is a stress fiber associated protein that is alternative spliced to generate uLIMCH1, a ubiquitously expressed isoform, and mLIMCH1, a skeletal muscle-specific isoform. mLIMCH1 contains 454 in-frame amino acids which are encoded by six contiguous exons simultaneously included after birth in mouse. The developmental regulation and tissue specificity of this splicing transition is conserved in mice and humans. To determine the physiologically relevant functions of mLIMCH1 and uLIMCH1, CRISPR-Cas9 was used to delete the genomic segment containing the six alternatively spliced exons of LIMCH1 in mice, thereby forcing the constitutive expression of the predominantly fetal isoform, uLIMCH1 in adult skeletal muscle. mLIMCH1 knockout mice had significant grip strength weakness in vivo and maximum force generated was decreased ex vivo. Calcium handling deficits were observed during myofiber stimulation that could explain the mechanism by which mLIMCH1 knockout leads to muscle weakness. Additionally, LIMCH1 is mis-spliced in myotonic dystrophy type 1 with the muscle blind-like (MBNL) family of proteins acting as the likely major regulator of Limch1 alternative splicing in skeletal muscle.
Postnatal skeletal muscle development is a highly dynamic period associated with widespread alternative splicing changes required to adapt tissues to adult function. These splicing events have significant implications because the reversion of adult mRNA isoforms to fetal isoforms is observed in forms of muscular dystrophy. LIMCH1 is a stress fiber–associated protein that is alternatively spliced to generate uLIMCH1, a ubiquitously expressed isoform, and mLIMCH1, a skeletal muscle–specific isoform containing six additional exons simultaneously included after birth in the mouse. CRISPR/Cas9 was used to delete the six alternatively spliced exons of LIMCH1 in mice, thereby forcing the constitutive expression of the predominantly fetal isoform, uLIMCH1. mLIMCH1 knockout mice had significant grip strength weakness in vivo, and maximum force generated was decreased ex vivo. Calcium-handling deficits were observed during myofiber stimulation that could explain the mechanism by which mLIMCH1 knockout leads to muscle weakness. In addition,LIMCH1is mis-spliced in myotonic dystrophy type 1, with the muscleblind-like (MBNL) family of proteins acting as the likely major regulator ofLimch1alternative splicing in skeletal muscle.
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