In Situ Altering of the Extracellular Matrix to Direct the Programming of Endogenous Stem Cells


  • Tzu-Min Chan,

    1. Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan, Republic of China
    2. Everfront Biotech, Inc., New Taipei City, Taiwan, Republic of China
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  • Hui-Ping Lin,

    1. Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan, Republic of China
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  • Shinn-Zong Lin

    Corresponding author
    1. Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan, Republic of China
    2. Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan, Republic of China
    3. Department of Neurosurgery, Tainan Municipal An-Nan Hospital-China Medical University, Tainan, Taiwan, Republic of China
    4. Graduate Institute of Immunology, China Medical University, Taichung, Taiwan, Republic of China
    • Correspondence: Shinn-Zong Lin, M.D., Ph.D., Center for Neuropsychiatry, China Medical University Hospital, Taichung, Taiwan, Republic of China. Telephone: 886-4-22052121, ext. 6034; Fax: 886-4-220806666; e-mail:

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Dear Editor:

Scientific interest in the extracellular matrix (ECM) has grown in recent years, due to the potential of the ECM to act as a niche for stem cell self-renewal [1], and also for its ability to regulate cell fate (depending on ECM components) in an in vitro culture system [2]. The ECM provides structural support for cells by serving as a framework or an environmental niche, thereby facilitating the programming and orchestration of many cellular processes, including differentiation. One recent report, entitled “Defined Extracellular Matrix Components Are Necessary for Definitive Endoderm Induction,” indicated that the assembly of fibronectin and laminin in the ECM is correlated with the successful differentiation of embryoid bodies into definitive endoderm [3]. In addition, in vitro modulation of cellular interactions and signaling can positively regulate osteogenesis [2]. This is achieved through signaling pathways, growth factors, and functional three-dimensional (3D) scaffolds that are assembled into a matrix. Similarly, the ECM can be used to create a responsive niche for skeletal muscle satellite cells [4]. These satellite cells serve as tissue-specific precursors in subsequent myogenic programming, thereby enabling the cells to remain quiescent until they respond to signals of muscular damage. Moreover, the pluripotency of human embryonic stem cells can be preserved within the ECM, allowing for pluripotent gene expression, specifically, changing ECM components to differentiate into endodermal, mesodermal, and ectodermal progenitors [5]. Thus, the ECM is important for controlling the status of stem cells and enabling their feasible cell fates.

An important issue in cell-based regenerative medicine is whether differentiated cells cultured in a specific ECM have in vivo therapeutic potential in disease relevant animals [6]. Taylor-Weiner et al. [3] provided an experimental approach in which the definitive fate of endoderm cells was directed in a well-organized niche. However, the authors appeared to be unconcerned with whether cell lines could be differentiated, for example, into hepatocytes [7] or insulin-secreting cells [8]. Additionally, cells cultured in the ECM should be able to perform the standard functions of differentiated cells, and the therapeutic potential should be tested using animal models. For example, in mice with type 2 diabetes, insulin-secreting differentiated cells were shown to have significantly lower serum glucose levels and higher human insulin and c-peptide levels than undifferentiated cells [9]. Moreover, differentiated neural cells have proven effective in animal models and have also been shown to secrete both dopamine and serotonin [10]. Thus, in future work, authors should perhaps emphasize how the improved microenvironment niche can be used to achieve more specific differentiation of cell lineages, and then address transplant therapy of these cells. Additional reports detailing successful treatments in animal investigations would also provide further support of the applicability through in vivo modification of the ECM.

Major issues in transplant medicine include the difficulty of transplanting stem cells into damaged tissue, reduced neuroplasticity, poor integration of stems cells, and the fact that transplanted stem cells tend not to remain in the area of the injury following transplantation. The suitability of stem cells to target tissues depends primarily on the capacity of the microenvironment, which makes developing a microniche to ensure the in vivo functional recovery of transplanted cells that is important for transplant medicine [11]. One prominent experimental design that removal of defect from lateral gastrocnemius following implanted Mesenchymal stem cells-seeded muscle-derived ECM [12]. The result showed that removed area had outstanding recovery of blood vessels and regenerating skeletal myofibers in traumatic skeletal muscle injury rats. With regard to neuroplasticity, a number of ECM components have been found to enhance the growth of regenerative axons and the formation of nerve fascicles, such as laminins, fibronectins, and collagen type IV [13]. Recently, Higuera et al. [14] sought to develop a 3D well-system, in which they screened suitable ECM components for the regeneration of tissue. These researchers proposed evaluating the in vivo conditions of the ECM as an alternative to using an animal model. In summary, the in vivo alteration of the ECM has been shown to be a suitable method for prolonging the survival of transplanted cells, enhancing the accuracy of differentiation into tissue-specific lineages, and facilitating structural and functional recovery such as muscular integration [12] and synaptic plasticity [15].

The ECM can be remodeled to create a microenvironment niche capable of controlling functional integration and outcome [16, 17]. This process can also be used to inhibit tumorigenicity in undifferentiated transplanted cells [5]. One achievable goal may be the direct programming of endogenous stem cells into tissue-specific lineages [18]. The in situ alteration of the ECM has also shown considerable promise in enhancing stem cell homing [19], thereby improving the effectiveness of cell-based therapy. In addition, autologous hematopoietic stem cells (HSCs) in bone marrow have the capacity to differentiate into most cell lines [20]. However, they seldom end up in peripheral tissue, where endogenous peripheral stem cells are already scarce [21]; therefore, granulocyte colony-stimulating factors (GCSFs) are necessary to recruit HSCs [22]. Besides, an additional remarkable feature of homing in vivo endogenous stem cells is to prevent harm caused by transplanting in vitro amplified cells, such as microbial threats, cytotoxicity, unstable biological activities, and genetic or epigenetic instability [23]. Thus, combining the in situ modification of the ECM with the use of GCSFs may be an effective and safe method of transporting HSCs to tissues requiring treatment.

Author Contributions

T.-M.C. and H.-P.L. provided equal contributions to this work. T.-M.C and H.-P.L: Conception and design, manuscript writing; S.-Z.L.: Conception and design, final approval of manuscript.

Disclosure of Potential Conflicts of Interest

The authors indicate no potential conflicts of interest.