## 4 The Future--Where Are We Going?
As compared to autogenic cells, the allosteric sources are considered to be more available cells with fewer problems in terms of developing commercial products [371]. The use of ESCs offer an unlimited supply of cells with the ability to differentiate into the osteogenic lineage. However, there are some specific barriers that prevent their widespread use including ethical issues and tumorigen risk. The development of iPSCs is the intelligent way to have the advantages as well as remove the disadvantages of ESCs. After being introduced by Professor [PERSON], more attention has been paid to use hiPSc for repair of bone diseases and damages [372]. Some studies clarified that these cells are comparable in vivo bone regeneration and angiogenic capability to hBMSCs and hUCMSCs on rats [373]. However, no clinical trials have been conducted using these cells for bone-related disorders. As an optimal cell source for BTE, MSCs derived from different origins (bone marrow and adipose) have been used for BTE applications more than other cell types. These cells through the secretion of various therapeutic factors show an excellent ability to accelerate bone healing [374]. It is worth noting that the term of 'Medicinal Signaling Cell' is recently proposed by Professor [PERSON] instead of 'Mesenchymal stem cell' [375]. He believes that \"these cells do not function in the body as progenitors for tissues, neither in the normal steady-state nor in disease or injury circumstances. They are not stem cells.\" The reason for this newly suggested term is related to the secretion of bioactive molecules as therapeutic drugs from MSCs to the micro-environment providing an in situ medicinal condition for the patient's own site-specific and tissue-specific resident stem cells that construct the new tissue. These bioactive molecules are comprised of various growth factors, cytokines, and chemokines that exert anti-apoptotic, immunomodulatory, anti-scarring, supportive, angiogenic, and chemoattractant effects (Figure 11). From the regeneration point of view, there are differences among various stem cells derived from mesenchymal tissues. For example, it has been reported that BM-MSCs have higher osteogenic potential as compared to MSCs and UC-MSCs in a rat's calvarial defect [169]. However, the isolation and culturing procedures of BM-MSCs are time-consuming and overwhelming processes. In conclusion, the final aim of each experimental study may provide the proof for using each cell type for a BTE application. Taking advantage of previously reported studies can be helpful for the researcher to select appropriate cell sources for their work, either animal or human trials. Historically, MSCs could be beneficial for accelerating the bone repair and regeneration. However, recent studies focus on the use of iPSCs as a reliable cell source for bone reconstruction. Nonetheless, it is too early to draw definite conclusions about the success of these cells, and additional clinical trials need to be conducted. A dramatic revolution has also recently arisen in the genome editing of human pluripotent stem cells (hPSC) with the advent of novel technologies like zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-nucleases. These technologies represent powerful tools to generate various cell types for targeted therapies and clinical transplantation. As a final point, the role of biomaterials includes the healing ability of cells when they are used simultaneously. In this regard, three-dimensional (3D) bio-printing as a cutting-edge technology could open up new horizons to clinicians for better utilization of cell- biomaterial constructs in the treatment of tissue injuries like bone damages. Accordingly, the understanding of the interactions between cells and different biomaterials is strongly suggested to get better results. Figure 11: Schematic representation of therapeutic molecules secreted by MSCs to accelerate bone healing.