A new function of a previously isolated compound that

stimulates activation and differentiation of myogenic

precursor cells leading to efficient myofiber
regeneration and muscle repair.
Cheng L, Gu X, Sanderson JE, Wang X, Lee K, Yao X, Liu H, Cheung WL, Li M.

Department of Medicine and Therapeutics, 9th Floor, Clinical Building, Prince of Wales
Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.

Muscle repair following severe injury is slow and incomplete due to the limited
regenerative capacity of muscles comprising the function. In this study, one pure
compound structurally corresponding to triterpenoid, which can directly induce the
activation, proliferation and maturation of quiescent satellite cells into myocytes in vitro,
was isolated from Geum japonicum. The potential effect of this compound on
myogenesis was further tested in repair of severe muscle injury. It was found that this
compound could significantly stimulate the regenerative potential of the damaged muscle
resulting in regeneration of myotubes and myotube bundles time-dependently replacing
the damaged muscle tissues. This compound-mediated active regeneration of new
myofibers repairing damaged muscles was probably due to its direct action on activation
and proliferation of quiescent myogenic precursor cells and enhancement of their
maturation into regenerating myotubes, as was demonstrated in our primary myogenic
precursor cells culture experiments. The up-regulated expression of endogenous phospho-
Akt1 in compound-treated myogenic precursor cells may also contribute to the process of
myofiber regeneration and muscle repair probably via promoting myogenic cell survival
capacity.

PMID: 16431151 [PubMed - indexed for MEDLINE]

: Development. 2007 Nov;134(22):3953-7. Links

Satellite and stem cells in muscle growth and

repair.
Le Grand F, Rudnicki M.

Sprott Center for Stem Cell Research, Ottawa Health Research Institute, 501
Smyth Road, Ottawa, ON K1H 8L6, Canada.
 The FASEB summer research conference on Skeletal Muscle Satellite and Stem
Cells, organized by Thomas Rando, Giulio Cossu and Jeffrey Chamberlain, was
held in Indian Wells, California, in July. An international array of researchers
gathered to share numerous new insights into the cellular and molecular
regulation of stem cells and satellite cells in skeletal muscle biology. The
conference is unique in that it brings together investigators from diverse
backgrounds, who work on the growth and repair of skeletal muscle in humans
and model systems, in health and disease.

PMID: 17965049 [PubMed - indexed for MEDLINE]

1: Physiol Rev. 2004 Jan;84(1):209-38. Links

Cellular and molecular regulation of muscle

regeneration.
Chargé SB, Rudnicki MA.

Ottawa Health Research Institute, Ottawa, Ontario, Canada.

Under normal circumstances, mammalian adult skeletal muscle is a stable tissue

with very little turnover of nuclei. However, upon injury, skeletal muscle has the
remarkable ability to initiate a rapid and extensive repair process preventing the
loss of muscle mass. Skeletal muscle repair is a highly synchronized process
involving the activation of various cellular responses. The initial phase of muscle
repair is characterized by necrosis of the damaged tissue and activation of an
inflammatory response. This phase is rapidly followed by activation of myogenic
cells to proliferate, differentiate, and fuse leading to new myofiber formation and
reconstitution of a functional contractile apparatus. Activation of adult muscle
satellite cells is a key element in this process. Muscle satellite cell activation
resembles embryonic myogenesis in several ways including the de novo induction
of the myogenic regulatory factors. Signaling factors released during the
regenerating process have been identified, but their functions remain to be fully
defined. In addition, recent evidence supports the possible contribution of adult
stem cells in the muscle regeneration process. In particular, bone marrow-derived
and muscle-derived stem cells contribute to new myofiber formation and to the
satellite cell pool after injury.

PMID: 14715915 [PubMed - indexed for MEDLINE]

1: Folia Histochem Cytobiol. 2006;44(2):75-9. Links

Contribution of stem cells to skeletal muscle

regeneration.
Kawiak J, Brzóska E, Grabowska I, Hoser G, Stremińska W, Wasilewska D,
Machaj EK, Pojda Z, Moraczewski J.

Dept. Clinical Cytology, Medical Centre of Postgraduate Education, Marymoncka

99, 01-813 Warsaw, Poland. jkawiak@cmkp.edu.pl

Stem cells for skeletal muscle originate from dermomyotome of the embryo. The
early marker of these cells is expression of both transcription factors Pax3 and
Pax7 (Pax3+/Pax7+ cells). The skeletal muscles in the adult organism have a
remarkable ability to regenerate. Skeletal muscle damage induces degenerative
phase, followed by activation of inflammatory and satellite cells. The satellite
cells are quiescent myogenic precursor cells located between the basal membrane
and the sarcolemma of myofiber and they are characterized by Pax7 expression.
Activation of the satellite cells is regulated by muscle growth and chemokines.
Apart from the satellite cells, a population of adult stem cells (muscle side
population--mSP) exists in the skeletal muscles. Moreover, the cells trafficking
from different tissues may be involved in the regeneration of damaged muscle.
Trafficking of cells in the process of damaged muscle regeneration may be traced
in the SCID mice.

PMID: 16805130 [PubMed - indexed for MEDLINE]

: Stem Cells. 2007 Apr;25(4):885-94. Epub 2007 Jan 11. Links

A population of myogenic stem cells that survives

skeletal muscle aging.
Collins CA, Zammit PS, Ruiz AP, Morgan JE, Partridge TA.

The Dubowitz Neuromuscular Unit, Department of Paediatrics, Imperial College

London, Hammersmith Hospital, London, U.K.
 Age-related decline in integrity and function of differentiated adult tissues is
widely attributed to reduction in number or regenerative potential of resident stem
cells. The satellite cell, resident beneath the basal lamina of skeletal muscle
myofibers, is the principal myogenic stem cell. Here we have explored the
capacity of satellite cells within aged mouse muscle to regenerate skeletal muscle
and to self-renew using isolated myofibers in tissue culture and in vivo. Satellite
cells expressing Pax7 were depleted from aged muscles, and when aged
myofibers were placed in culture, satellite cell myogenic progression resulted in
apoptosis and fewer total differentiated progeny. However, a minority of cultured
aged satellite cells generated large clusters of progeny containing both
differentiated cells and new cells of a quiescent satellite-cell-like phenotype
characteristic of self-renewal. Parallel in vivo engraftment assays showed that,
despite the reduction in Pax7(+) cells, the satellite cell population associated with
individual aged myofibers could regenerate muscle and self-renew as effectively
as the larger population of satellite cells associated with young myofibers. We
conclude that a minority of satellite cells is responsible for adult muscle
regeneration, and that these stem cells survive the effects of aging to retain their
intrinsic potential throughout life. Thus, the effectiveness of stem-cell-mediated
muscle regeneration is determined by both extrinsic environmental influences and
diversity in intrinsic potential of the stem cells themselves.

PMID: 17218401 [PubMed - indexed for MEDLINE]

Stem and progenitor cells in skeletal muscle

development, maintenance, and therapy.
Péault B, Rudnicki M, Torrente Y, Cossu G, Tremblay JP, Partridge T, Gussoni E,
Kunkel LM, Huard J.

Stem Cell Research Center, Children's Hospital of Pittsburgh, Department of Orthopaedic

Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

Satellite cells are dormant progenitors located at the periphery of skeletal myofibers that
can be triggered to proliferate for both self-renewal and differentiation into myogenic
cells. In addition to anatomic location, satellite cells are typified by markers such as M-
cadherin, Pax7, Myf5, and neural cell adhesion molecule-1. The Pax3 and Pax7
transcription factors play essential roles in the early specification, migration, and
myogenic differentiation of satellite cells. In addition to muscle-committed satellite cells,
multi-lineage stem cells encountered in embryonic, as well as adult, tissues exhibit
myogenic potential in experimental conditions. These multi-lineage stem cells include
side-population cells, muscle-derived stem cells (MDSCs), and mesoangioblasts.
Although the ontogenic derivation, identity, and localization of these non-conventional
myogenic cells remain elusive, recent results suggest their ultimate origin in blood vessel
walls. Indeed, purified pericytes and endothelium-related cells demonstrate high
myogenic potential in culture and in vivo. Allogeneic myoblasts transplanted into
Duchenne muscular dystrophy (DMD) patients have been, in early trials, largely
inefficient owing to immune rejection, rapid death, and limited intramuscular migration--
all obstacles that are now being alleviated, at least in part, by more efficient
immunosuppression and escalated cell doses. As an alternative to myoblast
transplantation, stem cells such as mesoangioblasts and CD133+ progenitors
administered through blood circulation have recently shown great potential to regenerate
dystrophic muscle.

PMID: 17387336 [PubMed - indexed for MEDLINE]

J Cell Biol. 2002 Oct 14;159(1):123-34. Epub 2002 Oct 14.

Links

Myogenic specification of side population cells in

skeletal muscle.
Asakura A, Seale P, Girgis-Gabardo A, Rudnicki MA.

Molecular Medicine Program, Ottawa Health Research Institute, Ottawa, Ontario,

K1H 8L6 Canada.

Skeletal muscle contains myogenic progenitors called satellite cells and muscle-
derived stem cells that have been suggested to be pluripotent. We further
investigated the differentiation potential of muscle-derived stem cells and satellite
cells to elucidate relationships between these two populations of cells. FACS(R)
analysis of muscle side population (SP) cells, a fraction of muscle-derived stem
cells, revealed expression of hematopoietic stem cell marker Sca-1 but did not
reveal expression of any satellite cell markers. Muscle SP cells were greatly
enriched for cells competent to form hematopoietic colonies. Moreover, muscle
SP cells with hematopoietic potential were CD45 positive. However, muscle SP
cells did not differentiate into myocytes in vitro. By contrast, satellite cells gave
rise to myocytes but did not express Sca-1 or CD45 and never formed
hematopoietic colonies. Importantly, muscle SP cells exhibited the potential to
 give rise to both myocytes and satellite cells after intramuscular transplantation.
In addition, muscle SP cells underwent myogenic specification after co-culture
with myoblasts. Co-culture with myoblasts or forced expression of MyoD also
induced muscle differentiation of muscle SP cells prepared from mice lacking
Pax7 gene, an essential gene for satellite cell development. Therefore, these data
document that satellite cells and muscle-derived stem cells represent distinct
populations and demonstrate that muscle-derived stem cells have the potential to
give rise to myogenic cells via a myocyte-mediated inductive interaction.

PMID: 12379804 [PubMed - indexed for MEDLINE]

: Differentiation. 2001 Oct;68(4-5):245-53. Links

Muscle satellite cells are multipotential stem cells

that exhibit myogenic, osteogenic, and adipogenic
differentiation.
Asakura A, Komaki M, Rudnicki M.

Ottawa Health Research Institute, Ontario, Canada.

Muscle satellite cells are believed to represent a committed stem cell population
that is responsible for the postnatal growth and regeneration of skeletal muscle.
However, the observation that cultured myoblasts differentiate into osteocytes or
adipocytes following treatment with bone morphogenetic proteins (BMPs) or
adipogenic inducers, respectively, suggests some degree of plasticity within the
mesenchymal lineage. To further investigate this phenomenon, we explore the
osteogenic and adipogenic potential of satellite cells isolated from adult mice. Our
experiments clearly demonstrate that satellite cell-derived primary myoblasts,
expressing myogenic markers such as MyoD, Myf5, Pax7 and desmin,
differentiated only into osteocytes or adipocytes following treatment with BMPs
or adipogenic inducers, respectively However, satellite cells on isolated muscle
fibers cultured in Matrigel readily differentiated into myocytes as well as
osteogenic and adipogenic lineages, whereas primary myoblasts did not. Satellite
cell-derived primary myoblasts isolated from mice lacking the myogenic
transcription factor MyoD (MyoD-/-) differentiate into myocytes poorly in vivo
and in vitro (Megeney et al., Genes Dev. 1996; Sabourin et. al, J. Cell Biol.,
1999). Therefore, we tested whether MyoD-/- primary myoblasts display
increased plasticity relative to wild type cells. Unexpectedly, the osteogenic or
adipogenic differentiation potential of MyoD-/- primary myoblasts did not
 increase compared to wild-type cells. Taken together, these results strongly
suggest that muscle satellite cells possess multipotential mesenchymal stem cell
activity and are capable of forming osteocytes and adipocytes as well as
myocytes.

PMID: 11776477 [PubMed - indexed for MEDLINE]

1: Nature. 2008 Feb 21;451(7181):937-42.

Stem-cell therapy for cardiac disease.

Segers VF, Lee RT.

Cardiovascular Division, Department of Medicine, Brigham and Women's

Hospital, Harvard Medical School, Partners Research Facility, 65 Landsdowne
Street, Cambridge, Massachusetts 02139, USA.

Heart failure is the leading cause of death worldwide, and current therapies only
delay progression of the disease. Laboratory experiments and recent clinical trials
suggest that cell-based therapies can improve cardiac function, and the
implications of this for cardiac regeneration are causing great excitement. Bone-
marrow-derived progenitor cells and other progenitor cells can differentiate into
vascular cell types, restoring blood flow. More recently, resident cardiac stem
cells have been shown to differentiate into multiple cell types present in the heart,
including cardiac muscle cells, indicating that the heart is not terminally
differentiated. These new findings have stimulated optimism that the progression
of heart failure can be prevented or even reversed with cell-based therapy.

PMID: 18288183 [PubMed - in process]

: Cell. 2005 Jul 29;122(2):289-301. Links

Stem cell function, self-renewal, and behavioral

heterogeneity of cells from the adult muscle
satellite cell niche.
Collins CA, Olsen I, Zammit PS, Heslop L, Petrie A, Partridge TA, Morgan
JE.

Muscle Cell Biology Group, Medical Research Council Clinical Sciences Centre,
Imperial College Faculty of Medicine, Hammersmith Hospital, Du Cane Road,
London W12 ONN, UK. charlotte.collins2@csc.mrc.ac.uk

Satellite cells are situated beneath the basal lamina that surrounds each myofiber
and function as myogenic precursors for muscle growth and repair. The source of
satellite cell renewal is controversial and has been suggested to be a separate
circulating or interstitial stem cell population. Here, we transplant single intact
myofibers into radiation-ablated muscles and demonstrate that satellite cells are
self-sufficient as a source of regeneration. As few as seven satellite cells
associated with one transplanted myofiber can generate over 100 new myofibers
containing thousands of myonuclei. Moreover, the transplanted satellite cells
vigorously self-renew, expanding in number and repopulating the host muscle
with new satellite cells. Following experimental injury, these cells proliferate
extensively and regenerate large compact clusters of myofibers. Thus, within a
normally stable tissue, the satellite cell exhibits archetypal stem cell properties
and is competent to form the basal origin of adult muscle regeneration.

PMID: 16051152 [PubMed - indexed for MEDLINE]