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Review
. 2024 Oct 27:15:20417314241287491.
doi: 10.1177/20417314241287491. eCollection 2024 Jan-Dec.

Unlocking the regenerative key: Targeting stem cell factors for bone renewal

Gul Karima  1 , Hwan D Kim  1   2   3
Affiliations
Review

Unlocking the regenerative key: Targeting stem cell factors for bone renewal

Gul Karima et al. J Tissue Eng. .

Abstract

Stem cell factors (SCFs) are pivotal factors existing in both soluble and membrane-bound forms, expressed by endothelial cells (ECs) and fibroblasts throughout the body. These factors enhance cell growth, viability, and migration in multipotent cell lineages. The preferential expression of SCF by arteriolar ECs indicates that arterioles create a unique microenvironment tailored to hematopoietic stem cells (HSCs). Insufficiency of SCF within bone marrow (BM)-derived adipose tissue results in decreased their overall cellularity, affecting HSCs and their immediate progenitors critical for generating diverse blood cells and maintaining the hematopoietic microenvironment. SCF deficiency disrupts BM function, impacting the production and differentiation of HSCs. Additionally, deleting SCF from adipocytes reduces lipogenesis, highlighting the crucial role of SCF/c-kit signaling in controlling lipid accumulation. This review elucidates the sources, roles, mechanisms, and molecular strategies of SCF in bone renewal, offering a comprehensive overview of recent advancements, challenges, and future directions for leveraging SCF as a key agent in regenerative medicine.

Keywords: Stem cell factors; bone renewal; ligands; medicine; regeneration; viability.

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Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Growing interest in stem cell-based therapy in bone regeneration: (a) number of publications and, (b) number of citations per year related to keywords like bone regeneration, bone renewal, and bone repair using stem cells, (c) number of publications, and (d) number of citations per year related to keywords like stem cell factors, c-kit receptor, and SCF/c-kit.
Scheme 1.
Scheme 1.
Summary of the core aspects discussed in this review. The aspects include critical sources, functional properties, repairing and regenerative abilities, key roles in maintaining hematopoietic homeostasis, mechanisms in bone regeneration, clinical implications on disease therapy and limitations of SCFs. The crucial sources of SCF encompass a diverse array of tissues (brain, liver, kidney, lung, placenta, fibroblasts, etc.) and cellular (BM stromal). In vitro, SCFs singlehandedly promote the viability and self-performance of HSCs and play a crucial role in mast cell biology. There exist various potential applications of SCFs, including but not limited to improving dental pulp’s regenerative abilities, remodeling tissue and repair, facilitating 3D scaffold stem, cell transplant via mobilization, improving and exerting paracrine effects in the field of regenerative medicine. SCFs are important to help BM function properly for the production and differentiation of HSCs. The scarcity of SCFs affects the ability of BM to facilitate the HSC function, leading to development of hematological diseases. Mechanistically, SCF plays a pivotal role in bone repair by bridging BMA with the hematopoietic system and through their interactions with skeletal stem cells. SCFs are used in clinically to treat diseases such as aplastic anemia and skin disorders. SCFs are potential tools for regeneration and recovery of ischemic injuries. SCFs, despite showing great potential in regenerative medicine, possess several limitations including mast cell-driven cytotoxicity, challenges associated with available cell sources, poor quality biomaterials insufficient supply of blood and oxygen to defect sites and negative regulation of SCFs/c-kit signaling. These limitations need to be addressed to maximize the efficacy of SCFs.
Figure 2.
Figure 2.
Early postnatal BM shows HSCs adjacent to sinusoidal blood vessels. Both LepR+ and ECs display elevated SCF levels within the BM. Myeloerythroid progenitors such as CMP depend on LepR+ cell-derived SCF for activation, while ECs-derived SCF is essential for HSC maintenance during this early postnatal period.
Figure 3.
Figure 3.
The role of SCF in regeneration. (a) SCFs are administered into the pulp using a syringe after cleaning damaged tooth areas. The interaction between dental stem cells and SCF helps in the regeneration of dental pulp. (b) Mechanism for the regeneration of liver tissue. The combined effect of SCF, TGF-β and GM-CSF with their respective signaling pathways facilitates the liver cell proliferation and survival, which aid in inducing liver regeneration. (c) SCF facilitates the construction of scaffolds as a basis for tissue regeneration. The cocktail of stem cells and biological growth factors are introduced separately into the biomaterials of choice. Cocktail laden biomaterials are implanted symmetrically in vivo, enhancing tissue regeneration. (d) The paracrine effects of SCFs exerted on stem cells for activation and mobilization into blood circulation from BM. SCFs and G-CSF secreted by ECs act as mobilizing agents that activate dormant stem cells. The activated stem cells trespass into blood vessel form bone microenvironment.
Figure 4.
Figure 4.
SCF binds with its receptor c-kit present on the surface of HSCs, which then activates downstream signaling pathways vital for the survival and self-renewal. Downregulation of SCFs decreases activation inherent to this pathway, leading to impaired HSC maintenance and function loss. The c-kit signaling activates PI3K/Akt pathway, an important regulator of cell survival. Consider that failure to induce AKT by SCF could result in increased apoptosis and reduced HSC viability. SCF also upregulates the MAPK pathway, a key cellular signaling network that controls cell proliferation and differentiation. SCF-deficiency disrupts this pathway and the differentiation of HSC into multiple blood cell lineages is impaired.
Figure 5.
Figure 5.
The structure of bone and the interactions between cortical and trabecular (cancellous) bone, along with key cells in bone remodeling. Cortical bone is the compact outer layer and cancellous or spongy bone inside. The process shows how remodeling occurs in response to loading and unloading. Bone forming osteoblasts are activated, whereas old bone resorbing cells called osteoclasts get deactivated. Osteocytes, descendants of osteoblasts, support bone tissue and lining cells cover inactive areas on bones. These cells are regulated by signaling molecules to maintain the balance between bone formation and resorption. This figure is taken from article which can be distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).
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