Compositions and methods for modulating stem cells and uses thereof

Abstract

There are provided compositions and methods for modulating stem cell division decisions, in particular, division symmetry. It has been demonstrated that wnt7a acts through frizzled-7 receptor expressed on the surface of adult stem cells, e.g. satellite stem cells, to activate the planar cell polarity (PCP) pathway, thereby promoting symmetrical expansion of stem cells. The compositions and methods of the invention are useful, for example, in modulating stem cell division symmetry in vitro and in vivo, in replenishing and expanding the stem cell pool, and in promoting the formation, maintenance, repair and regeneration of tissue.

1 .- 95 . (canceled) 
     
     
         96 . A method for promoting tissue formation, growth, regeneration, maintenance or repair in a subject comprising administering to the subject a composition comprising (a) a Wnt7a polypeptide or an active variant, fragment, analogue or derivative thereof, or (b) a polynucleotide encoding a Wnt7a polypeptide or an active variant, fragment, analogue or derivative thereof. 
     
     
         97 . The method of  claim 96 , wherein the tissue is muscle. 
     
     
         98 . The method of  claim 96 , wherein the tissue is skeletal muscle. 
     
     
         99 . The method of  claim 97 , wherein the tissue formation, growth, regeneration, maintenance or repair comprises an increase in muscle fiber diameter. 
     
     
         100 . The method of  claim 96 , wherein the composition is formulated for injection. 
     
     
         101 . The method of  claim 100 , wherein the composition is formulated for one or more of intravenous injection, intramuscular injection, intracardiac injection, subcutaneous injection, or intraperitoneal injection. 
     
     
         102 . The method of  claim 96 , wherein the subject has a disease or condition affecting muscle. 
     
     
         103 . The method of  claim 102 , wherein the disease or condition affecting muscle is a wasting disease, muscular attenuation or atrophy, ICU-induced weakness, prolonged disuse, surgery-induced weakness, or a muscle degenerative disease. 
     
     
         104 . The method of  claim 103 , wherein the muscle degenerative disease is a muscular dystrophy. 
     
     
         105 . The method of  claim 96 , wherein muscular dystrophy is selected from Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), Emery-Dreifuss muscular dystrophy, Landouzy-Dejerine muscular dystrophy, facioscapulohumeral muscular dystrophy (FSH), Limb-Girdle muscular dystrophies, von Graefe-Fuchs muscular dystrophy, oculopharyngeal muscular dystrophy (OPMD), Myotonic dystrophy (Steinert's disease) and congenital muscular dystrophies. 
     
     
         106 . A method for promoting muscle cell hypertrophy in a subject comprising administering to the subject a composition comprising (a) a Wnt7a polypeptide or an active variant, fragment, analogue or derivative thereof, or (b) a polynucleotide encoding a Wnt7a polypeptide or an active variant, fragment, analogue or derivative thereof. 
     
     
         107 . The method of  claim 106 , wherein the muscle is skeletal muscle or cardiac muscle. 
     
     
         108 . The method of  claim 106 , wherein the hypertrophy is the result of increased muscle fiber diameter. 
     
     
         109 . The method of  claim 106 , wherein the subject has a disease or condition affecting muscle. 
     
     
         110 . The method of  claim 109 , wherein the disease or condition affecting muscle is a wasting disease, muscular attenuation or atrophy, ICU-induced weakness, prolonged disuse, surgery-induced weakness, or a muscle degenerative disease. 
     
     
         111 . A method of promoting adult stem cell expansion comprising contacting the adult stem cell with a composition comprising (a) a Wnt7a polypeptide or an active variant, fragment, analogue or derivative thereof, or (b) a polynucleotide encoding a Wnt7a polypeptide or an active variant, fragment, analogue or derivative thereof. 
     
     
         112 . The method of  claim 111 , wherein the adult stem cell is contacted ex vivo. 
     
     
         113 . The method of  claim 111 , wherein the adult stem cell is contacted in vivo. 
     
     
         114 . The method of  claim 111 , further comprising administering the contacted adult stem cells to a subject. 
     
     
         115 . The method of  claim 114 , wherein the composition is formulated for intravenous injection, intramuscular injection, intracardiac injection, subcutaneous injection, or intraperitoneal injection. 
     
     
         116 . The method of  claim 114 , wherein the subject has a disease or condition affecting muscle. 
     
     
         117 . The method of  claim 116 , wherein the disease or condition affecting muscle is a wasting disease, muscular attenuation or atrophy, ICU-induced weakness, prolonged disuse, surgery-induced weakness, or a muscle degenerative disease.