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Cell therapy is a kind of medicine aiming to cure disease or alleviate disease symptoms via direct infusion or transplantation of cells, which can be autologous or allogeneic. With several decades’ development and optimization, immuno-oncology cells (such as T cells, nature killer cells, etc.), stem cells (embryonic stem cells, induced pluripotent stem cells, progenitor cells, etc.) or other genetic re-engineered cells have been widely applied for cell therapy. Numerous cell types have been translated into clinical trials and promising cell therapy outcomes have been achieved from Phase I, Phase II and Phase III trials for a great number of diseases.

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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.

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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].

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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.


Table 5. Selected examples of disease therapy utilizing MSC [96]
DiseaseDelivery routeClinical trialsOutcomeReference
DiseaseDelivery routeClinical trialsOutcomeReference
Amyotrophic lateral sclerosis (ALS)IntrathecallyPhase INo adverse effects[97]
Amyotrophic lateral sclerosis (ALS)Intramuscularly, intrathecallyPhase I/IINo adverse effects[98]
Amyotrophic lateral sclerosis (ALS)IntrathecallyPhase INo adverse effects[99]
Amyotrophic lateral sclerosis (ALS)IntrathecallyPhase I/IIaNo adverse effects[100]
Multiple sclerosis (MS)IntravenouslyPhase I/IIIntial safety profile and feasibility of the intervention[101]
Multiple sclerosis (MS)IntravenouslyPhase I/IIaImprovement of visual acuity[102]
Multiple sclerosis (MS)IntravenouslyPhase I/IIaReduction in inflammation[103]
ALS/MSIntrathecally, intravenouslyPhase I/IIInduces rapid immunomodulatory effects[104]
Spinal cord injuryIntravenouslyPhase INo tumor development[105]
Spinal cord injuryLocally injectionPhase IIIVariable improvements in tactile sensitivity[106]
Spinal cord injuryintramedullary, subdurallyPhase IIIWeak therapeutic effect[107]
OsteoarthritisIntraarticularyPhase IImprovement of function and pain in high dose group[108]
OsteoarthritisIntraarticularyPhase IImprovement in pain levels in low dose group[109]
Graft-versus-host disease (GvHD)IntravenouslyPhase I/IINo adverse effects[110]
Graft-versus-host disease (GvHD)IntravenouslyPhase IImmunosuppressive therapy damaged intestinal epithelium[111]
Graft-versus-host disease (GvHD)IntravenouslyPhase I/IIClinical responses[112]
Crohn's diseaseIntravenouslyPhase INo adverse effects[113]
Crohn's diseaseIntravenouslyPhase IIReduce Crohn's disease activity index[114]
Liver failureIntravenouslyPhase I/IIReduce Model for End-stage Liver Disease (MELD) score[115]
Liver cirrhosisIntravenouslyPhase IImprovement in MELD score[116]
Kidney diseaseIntravenouslyPhase ISystemic immunosuppression[117]
Acute myocardial infarctionInfarcted sitesPhase I/IINo adverse effects[118]
Acute myocardial infarctionInfarct-related arteryPhase II/IIIModest improvement in left ventricular ejection fraction (LVEF) at 6-month follow-up[119]


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).

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


Table 6. Selected examples of disease therapy utilizing Progenitor Cells
DiseaseCell typesPhase of clinical trialsDelivery routeOutcomeReference
Ischemic CardiomyopathyCSCsPhase IintracoronaryLVEF increased, scar size reduced, life quality improved[134]
Ischemic Cardiomyopathycardiosphere-derived cells (CDCs)Phase IintracoronaryScar size reduced[135]
Ischemic CardiomyopathyCardiopoietic cellsPhase IItransendocardial stem cell injectionNo significance[136]
Nonischemic CardiomyopathyCD34+ stem cellPhase IIintracoronaryLVEF increased, function capacity improved[137], [138]
Macular degenerationhESC-derived retinal pigment epitheliumPhase I/IIsubretinal injectionincrease in subretinal pigmentation, vision-related life quality improved[132], NCT01344993
Stargardt's macular dystrophyhESC-derived retinal pigment epitheliumPhase I/IIsubretinal injectionincrease in subretinal pigmentation, vision-related life quality improved[132], NCT01345006
Amyotrophic lateral sclerosis (ALS)neural stem cellsPhase Iintraspinalwell tolerated[139]
Amyotrophic lateral sclerosis (ALS)neural stem cellsPhase Iintraspinalwell-tolerated[140]
Amyotrophic lateral sclerosis (ALS)neural stem cellsPhase Iintraspinalsafe[141]
Parkinson's diseasehuman parthenogenetic stem cell-derived NSCs (hpNSCs)Phase Istriatumdopamine levels increase[142]
Strokeneural stem cellsPhase Istereotactic ipsilateral putamen injectionneurological function improved[143]


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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