Stem Cell Therapy (ESC, MSC, IPSC, HSC in vivo transplantation)

Cell therapy based on stem cells is a kind of regenerative medicine with great potential for the treatment of diseases via the differentiation ability or the paracrine effects of stem cells as well as their derivatives. To date, a great number of cell types, have been applied from bench to bedside to treat diseases, such as cardiovascular diseases, neurodegenerative diseases and cancers. The cell types can be classified into three generations (Fig. 8): the 1st generation consists of skeletal myoblasts, bone marrow mononuclear cells (BMMNCs) and adipose-derived regenerative cells (ADRCs), mesenchymal stem cells (MSCs) and hematopoietic stem cells (CD34+/CD133+); the 2nd generation mainly utilizes embryonic stem cells (ESCs), induced pluripotent stem cells (iPS), cardiac stem cells (CSC) etc.; the next generation focuses on the combination therapy (CCT) of specific cell types, such as cell mixtures of cardiomyocytes, endothelial cells and smooth muscle cells.

Figure 8 Advance in stem cell therapy [91]. Three generations of cell types have been applied for disease therapy.

MSC

Mesenchymal stromal/stem cells (MSC) are stromal cells in almost all the tissues or organs, identified by the expression of a specific panel of cell surface markers (CD1051, CD731, CD901, CD34-, CD14-, or CD11b-, CD79- or CD19-, HLA-DR-) and the differentiation potentials into at least osteogenic, adipogenic, and chondrogenic lineages [92]. Although MSCs exist in almost all the human tissues, most of the MSCs used for clinical trials are isolated from bone marrow, adipose tissue and umbilical cord blood. And MSCs may have different biological characteristics and differentiation tendency according to their tissue sources as well as the isolation and culture procedures [93,94]. Based on the strong immunomodulatory, anti-inflammatory, and proregenerative capacities (Fig. 9) [95], MSCs have been promising candidates for the treatment of neurodegenerative diseases, Graft-versus-host disease (GvHD) and so on (Table 5) [96].

Figure 9 The regulatory effects of MSC on immune cells [95]. MSC can secret cytokines, such as IL-6, IL-8 and GM-CSF, promoting neutrophil migration to the infection/injury site and enhancing their activation and phagocytosis; MSC can also secrete other cytokines, like PGE2, IDO, HGF, CPG, IL-2, IL-4, IL-10, TGF-β1, adjusting the proliferation, differentiation, maturation and function of other immune cells.

ESCs/iPSCs or their derived cells

With the ability to self-renewal and differentiation into three germ layer derived lineages, embryonic stem cells (ESCs) [120-122] and induced pluripotent stem cells (iPSCs) [123,124] were thought to be invaluable candidates for disease regenerative therapy, especially iPSCs with no or mild immunological rejection (Fig. 10). However, their tumorigenicity greatly limits the direct transplantation of ESCs/iPSCs to treat disease [125]. Then lineage directed progenitor cells, such as neural progenitor/stem cells [126] and cardiac progenitor/stem cells [127], or terminally differentiated cells, such as cardiomyocytes [128,129], endothelial cells [130], smooth muscle cells [131], and retinal pigment epithelium[132] have been widely used in the therapy of a variety of diseases (Table 6).

Figure 10 Schematic for the generation and medical applications of induced pluripotent stem cells (iPSCs) [133].

Other Cell Therapy

Cell Combination Therapy (CCT) is also a promising therapy with the combination of several cell types, resulting in better therapy outcomes covering the advantages of different cell types. The combination of autologous CSCs and MSCs displayed better cardioreparative effects on swine ischemic cardiomyopathy model than that of MSCs [144,145]. Tri-lineage cell transplantation (cardiomyocytes, endothelial cells, and smooth muscle cells) displayed significant cardiac repair effects in the porcine acute myocardial infarction model by improving left ventricular function, myocardial metabolism, and arteriole density, as well as reducing infarct size and cardiomyocyte apoptosis [146]. Moreover, numerous biocompatible scaffolds, such as hydrogels [147], were used to facilitate the grafts integration in the compromised disease microenvironment and improve the survival of transplanted cells [148], which might significantly promote the clinical application of cell therapy.

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AAV(Adeno-Associated Virus) vector system

AAV1 vector system AAV2 vector system AAV2 variant(Y444F) vector system AAV2 variant (Y272F,Y444F,Y500F,Y730F) vector system AAV2 variant(Y444F,Y730F,Y500F,Y272F,Y704F,Y252F) vector system AAV2 variant(AAV2.7m8) vector system AAV5 vector system AAV6 vector system AAV8 vector system AAV8-1m vector system AAV8-2m vector system AAV8-3m vector system

AAV9 vector system AAV-Rh10 vector system AAV-DJ vector system AAV-Dj8 vector system AAV2-Retro (Retrograde) vector system AAV9-PHP.B vector system AAV9-PHP.eB vector system AAV9-PHP.S vector system AAV-BR1 vector system AAV-2i8 vector system AAV-SIG vector system AAV-VEC vector system

AAV Rep-Cap plasmids (serotypes-specific AAV RC plasmids)

AAV1 Rep-Cap Plasmid AAV2 Rep-Cap Plasmid AAV2 variant (Y444F) Rep-Cap plasmid AAV2 variant (Y272F, Y444F, Y500F, Y730F) Rep-Cap plasmid AAV2 variant (Y444F, Y730F, Y500F, Y272F, Y704F, Y252F) Rep-Cap plasmid AAV2 variant(AAV2.7m8) Rep-Cap plasmid AAV5 Rep-Cap Plasmid AAV6 Rep-Cap Plasmid AAV8 Rep-Cap Plasmid AAV8-1m Rep-Cap plasmid AAV8-2m Rep-Cap plasmid AAV8 variant (Y733F, Y447F, Y275) Rep-Cap plasmid

AAV9 Rep-Cap Plasmid AAV-Rh.10 Rep-Cap Plasmid AAV-DJ Rep-Cap Plasmid AAV-DJ/8 Rep-Cap Plasmid AAV-Retro (Retrograde) Rep-Cap plasmid AAV9-PHP.B Rep-Cap plasmid AAV9-PHP.eB Rep-Cap plasmid AAV9-PHP.S Rep-Cap plasmid AAV-BR1 Rep-Cap plasmid AAV-2i8 Rep-Cap plasmid AAV-SIG Rep-Cap plasmid AAV-VEC Rep-Cap plasmid