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International Journal of Bioprinting Bioprinted stem cell niche regenerates muscles

observed in both aged muscles and dystrophic muscles of Therefore, engineering an artificial microenvironment
patients with Duchenne muscular dystrophy (DMD) [1,2] . that has some similarities to native stem cell niches could
Therefore, transplantation of muscle stem cells has been represent a promising strategy to improve the efficacy and
widely studied for improving the regeneration of injured or survivability of stem cells transplanted into diseased or
diseased skeletal muscles [3-5] . However, poor cell survival injured muscles, such as dystrophic muscle. The efficiency
and self-renewal, rapid loss of stemness, high occurrence of stem cell transplantation depends largely on the number
of fibrogenesis, and limited dispersion of grafted cells of cells that survive transplantation and maintain the
away from the site of injection following transplantation regeneration potential of those cells. Notch activation is
have collectively hindered the overall success of this effective for repressing apoptosis [15,16] and fibrogenesis ,
[17]
strategy [6-10] . Therefore, for successful clinical translation, promoting angiogenesis [18,19] , and maintaining the self-
new strategies are needed to improve the efficacy of stem renewal capacity of muscle stem cells [23-25] . Notch activation
cell transplantation for the treatment of diseased muscle. is also a key molecular signature of native stem cell niches in
In DMD patients, despite the lack of dystrophin at skeletal muscle and is required for the colonization of stem
birth, clinical signs and symptoms of muscle weakness do cells within the niche and asymmetric cell division [21,26,27] . A
not become apparent until the patient reaches the age of recent study of two exceptional Golden retriever muscular
4–8 years which happens to coincide with the depletion dystrophy (GRMD) dogs that escaped from the severe
of the muscle stem cell pool . These observations suggest phenotype associated with dystrophin deficiency revealed
[1]
that preventing the depletion of the stem cell pool may that Jagged1, a Notch ligand, is upregulated in mildly affected
[28]
represent a novel approach to improve muscle strength dystrophin-deficient dogs . Based on these observations,
in patients with DMD despite the lack of dystrophin Notch activation seems to be a promising strategy for the
expression. healing of dystrophic muscle. In our previous studies, muscle
progenitor cells (MPCs) were effectively isolated from
Notch signaling is more activated in younger skeletal skeletal muscle using a modified preplate technique , and
[29]
muscle, but declines as muscle ages [11-13] . Notch activity in these cells were proven to be highly effective in promoting
dystrophic muscle was shown to be decreased . Also, our the regeneration of multiple tissue types after transplantation
[14]
preliminary data demonstrated decreased Notch activity in both skeletal and cardiac muscle [3,30,31] .
in skeletal muscle of mdx mice compared to normal
mice. Therefore, the lack of activated Notch signaling in Three-dimensional printing facilitates the application of
dystrophic muscle should be considered when performing scaffold-based or scaffold-free tissue and organ constructs,
stem cell therapy for DMD. mini-tissues, and organ-on-a-chip model system. Using a 3D
Notch is a crucial molecular regulator of stem cell bioprinter allows for the proper distribution and positioning
of biomaterials, signaling factors, and heterogeneous cells in
activity in skeletal muscle. In addition to maintaining high densities to form tissue engineering constructs (TECs).
proper function of the stem cell niche, Notch activation is Moreover, 3D-bioprinted constructs with interconnected
also able to repress apoptosis [15,16] and fibrogenesis , and pores and large surface areas support cell attachment,
[17]
promote angiogenesis [18,19] of many cell types. Although growth, intercellular communication, and exchange of gas
these concepts of Notch in stem cell niches have been well and nutrients. Compared with the conventional postcell
established and proven in the laboratory, the practical seeding approach, bioprinting achieved a close connection
application of these concepts has never been implemented between materials and cells, resulting in higher cell-loading
in the treatment of muscle diseases. efficiency and more homogenous cell distribution within the
Stem cell niches in skeletal muscle are “nests” of constructs [32-34] . According to different forming principles
quiescent stem cells beneath the basal lamina of myofibers and printing materials, biological 3D printing process can
and are critical for other cells to interact with the stem cells be divided into vat polymerization, material extrusion,
to maintain them or promote their differentiation . When material jetting, etc. Although the extrusion-based
[20]
skeletal muscle is damaged, stem cells within the niche are bioprinting approach is a commonly used technique for
activated to proliferate via asymmetric division . Some of fabrication of 3D complex tissue constructs due to its wide
[21]
these cells migrate toward the site of injury to participate range of printable materials and rapid fabrication speed, the
in muscle regeneration while other cells remain within the drop-on-demand material jetting approach is attractive for
niche to maintain the stem cell pool [20,21] . Maintenance of the contactless deposition and patterning of different types of
stem cell niche therefore determines muscle regeneration living cells and biomaterials within each layer to achieve
potential. In diseased or aged muscles, the functions of improved cell–cell and cell–matrix interactions [35-38] , which
stem cell niches are impaired, resulting in the loss of self- was therefore applied in our study of new strategies to
renewal and regeneration capacities of stem cells [20,22] . improve the regeneration of dystrophic muscle.

Volume 9 Issue 3 (2023) 300 https://doi.org/10.18063/ijb.711