Fibrosis is mainly characterized by parenchymal cell destruction, local activation of fibroblasts, and excessive accumulation of extracellular matrix (ECM) which results in loss of normal architecture and function of nearly all major organs including lung, heart, liver, skin, and kidney (Zeisberg and Kalluri, 2013; Nanthakumar et al., 2015; Vijayaraj et al., 2019). In the early stages, fibrosis is thought to be reversible, but with disease progression, it can lead to organ dysfunction and death (Wynn and Ramalingam, 2012; Zeisberg and Kalluri, 2013). Since there are still no effective treatments that can halt or reverse this pathological process, stem cell-based therapy seems to bring new hopes for patients with fibrotic diseases due to their abilities to self-renew and differentiate into different cell types that may replace or regenerate the dysfunctional organ (Blanpain and Fuchs, 2014; Vijayaraj et al., 2019; Cao et al., 2020).

Pluripotent stem cells (PSCs) include induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs). The above cells can self-renew and differentiate into ectoderm, mesoderm, and endoderm derivatives. (Dvash et al., 2007; Takahashi et al., 2007). iPSCs are pluripotent stem cells that are produced by the gene transfer of reprogramming factors to human somatic cells, which was first developed by Shinya Yamanaka and his team in 2006 (Takahashi and Yamanaka, 2006). In 2013, Yamanaka won the Nobel Prize in Physiology or Medicine for revealing that adult cells can be reprogrammed. The pluripotency of iPSCs is induced by a combination of reprogramming factors such as OCT3/4, SOX2, KLF4, c-MYC, and LIN28 (Okita et al., 2013; Parrotta et al., 2020). Because iPSCs are readily available, suitable for mass production, and eliminate immune rejection, iPSCs could be a promising alternative to ESCs (Fan et al., 2020).

Induced pluripotent stem cell (iPSC) is thought to be an important resource in regenerative medicine because of their pluripotency and self-renewal ability (Kamiya et al., 2019). Since the development of iPSC technology (Takahashi and Yamanaka, 2006), iPSCs have become one of the most promising sources of stem cells in the cell therapy application of organ fibrosis (Alvarez-Palomo et al., 2020; Fan et al., 2020; Bian et al., 2021; Nuciforo and Heim, 2021). As previously reported, iPSCs and iPSCs-derived epithelial cells, macrophages, cardiomyocytes (CMs), and endothelial cells had a potential influence in repairing damaged tissue in organs and tissue fibrosis (Dai et al., 2011; How et al., 2013; Alvarez-Palomo et al., 2020; Pouyanfard et al., 2021). For instance, the transplantation of iPSCs or iPSCs-derived alveolar epithelial cells could reduce lung fibrosis in pulmonary fibrosis (PF) model mouse (How et al., 2013; Alvarez-Palomo et al., 2020). And the iPSCs-derived macrophage populations could reduce fibrogenic gene expression and disease-associated histological markers in liver fibrosis model mouse (Pouyanfard et al., 2021). What’s more, iPSCs significantly improve the potential of developing personalized cell-based therapy for diseases like cystic fibrosis, since iPSCs can differentiate into patient-specific stem cells and repair tissues damaged by disease pathology (Suzuki et al., 2016).

In this review, we mainly summarize the iPSC-based therapeutic approaches for treating organ fibrosis (Figure 1; Supplementary Table S1), the advantages and disadvantages of iPSCs compared with other therapies, and the challenges and future outlook in this field.

Some fibrotic diseases including congenital hepatic fibrosis (CHF) and cystic fibrosis are closely related to genetic mutations. The gene-editing iPSCs may bring great hope to individualized or precision therapies for the above diseases. CHF is a rare inherited disorder caused by mutations in the PKHD1 gene with abnormal proliferation of cholangiocytes and variable degrees of periportal fibrosis (Tsunoda et al., 2019; Hasbaoui et al., 2021). Researchers knock out PKHD1 in iPSCs-derived hepatic progenitor-like cells to successfully establish a CHF disease model. And they revealed that the loss of fibrocystin encoded by PKHD1 triggers the proliferation of cholangiocytes through increased production of connective tissue growth factor (CTGF) and interleukin 8 (IL-8), moreover, IL-8 and CTGF levels were also significantly higher in the liver of patients with CHF which strongly indicated that CTGF and IL-8 will be novel therapeutic targets for the prevention of CHF (Tsunoda et al., 2019; Hasbaoui et al., 2021) (Supplementary Table S2).

Cystic fibrosis is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a chloride channel that regulates the balance of salt and water in secretory epithelial cells (Ruan et al., 2019; Merkert et al., 2020). It is the most common life-limiting, autosomal recessive monogenic disease in Caucasian populations (Farrell et al., 2008; Cantin et al., 2015). CFTR encodes an ion channel that is mainly expressed in the secretory epithelial cells of the airway, intestine, liver, and other tissues (Engels et al., 2019). Although cystic fibrosis influences multiple organs, progressive airway remodelling, mucus accumulation, and chronic inflammation of the lung leading to respiratory failure are the major cause of morbidity and mortality (Nuciforo and Heim, 2021). Past studies have generated cell lines related to F508del mutation (Fleischer et al., 2018; Kondrateva et al., 2020; Kondrateva et al., 2021a; Kondrateva et al., 2021b), Asn1303Lys mutation (Merkert et al., 2020), and S308X mutation (Khor et al., 2022) with human iPSCs derived from cystic fibrosis patients. These iPSC lines derived from the somatic cells of cystic fibrosis patients provide useful resources for disease modelling and research on the pharmacological response to CFTR regulators. In particular, iPSC cell lines carrying nonsense mutations could bring therapeutic hope to patients with extremely rare mutation types. Besides, several studies have used CRISPR, zinc-finger nuclease-mediated homology-directed repair, small/short DNA fragments, and sequence-specific TALENs to precisely correct mutations responsible for cystic fibrosis in patient iPSCs-derived epithelial cells (Crane et al., 2015; Firth et al., 2015; Suzuki et al., 2016; Merkert et al., 2017). Previous research presented directional differentiation of human iPSCs into airway basal cells (iBCs), a population similar to airway epithelial stem cells. Hawkins et al. corrected the F508del CFTR mutation by gene editing and finally revealed that the correction of the F508del mutation resulted in the restoration of the CFTR-dependent current (Hawkins et al., 2021). These discoveries showed that these gene-editing iPSCs-derived airway epithelial may be applied to the disease models and promote the development of iPSC-based cell therapies (Firth et al., 2015; Suzuki et al., 2016; Hawkins et al., 2021) (Supplementary Table S2) In general, researchers use gene-editing iPSCs to create disease models that mimic the pathology of human diseases. By studying these models, researchers may gain insights into the mechanisms behind the disease and identify potential drug targets.

PSCs including iPSCs and ESCs. All of the above cells can self-renew and differentiate into ectoderm, mesoderm, and endoderm derivatives. Human iPSCs used as alternative sources of PSCs have the same differentiation potential to transform into several lineages as ESCs. These properties make them very promising in drug screening, disease modeling, and regenerative medicine (Dvash et al., 2007). However, ESCs are derived from human embryos with limited supplements, and there are ethical issues related to embryos, which will limit the wide application of ESCs in clinical. But human iPSCs can be easily obtained by reprogramming patient-specific cells, which is suitable for mass production. By not involving embryos, some ethical issues can be avoided, and can be applied to personalized medicine. Moreover, ESCs also have safety problems related to immune rejection (Omole and Fakoya, 2018). The development of iPSCs reduces the risk of immune rejection because if the donor and the recipient are the same patients, immune rejection can be avoided (Nicolas et al., 2016; Guha et al., 2017). However, because iPSCs are reprogrammed from somatic cells, they may carry some undesirable mutations or epigenetic changes, while ESC is unlikely to have such problems (Liu et al., 2018; Parrotta et al., 2020). In general, human iPSCs may be the preferred choice because of their availability and lack of potential ethical concerns associated with human ESCs (Fan et al., 2020).

Mesenchymal stem cells (MSCs) are multipotent stromal progenitor cells that are heterogeneous, can self-renew, and transform into several lineages (Rastegar et al., 2010). MSCs can be obtained and isolated from a variety of tissues, such as bone marrow, skin, adipose tissue, umbilical cord blood, amniotic fluid, and placenta, of which bone marrow is the main source (Rastegar et al., 2010). Both the iPSCs and MSCs can easily be obtained and have the potential to differentiate into multiple lineages including osteoblastic, chondrogenic, adipogenic, neuronal, and cardiomyogenic lineages (Rastegar et al., 2010; Singh et al., 2015; Zomer et al., 2015). And both of them have a potential for potential tumorigenicity and the risk of chromosome aberration and genetic instability (Karnoub et al., 2007; Okita et al., 2008; Barkholt et al., 2013; Liu et al., 2018; Parrotta et al., 2020). Compared with the low reprogramming efficiency of iPSCs, the advantages of MSCs include that they can be produced on a larger scale and can be widely used in clinical applications such as neurodegenerative diseases, skin diseases, and liver diseases (Scudellari, 2016; Shin et al., 2017; Nasiri et al., 2019; Boika et al., 2020). Human iPSCs are stable at low temperatures without loss of function. Nevertheless, MSCs may experience replicative senescence, which may be related to the lack of telomerase activity, the decrease of cell proliferation of MSCs, and the reduction of differentiation potential of osteogenic and chondrogenic (Stenderup et al., 2003; Zhao et al., 2019; Fan et al., 2020). Furthermore, compared with MSCs, human iPSCs can be readily obtained by reprogramming patient-specific cells and avoiding immune rejection, because the donor and the recipient are the same patients, which may be used for precision therapy in organ fibrosis (Singh et al., 2015; Shi et al., 2017). The previous study demonstrated improved cardiac function with decreased fibrosis in both human iPSCs-CMs and human MSCs groups when compared with the MI group. And cardiac fibrosis was decreased in the human iPSCs-CM group when compared to the human MSCs (Citro et al., 2014). However, the exact mechanism of human iPSCs-CMs reducing cardiac fibrosis needs further study.

Ninety percent of patients with cystic fibrosis now benefit from small-molecule targeted therapies including Kalydeco (ivacaftor), Orkambi (lumacaftor/ivacaftor), Symdeko (tezacaftor/ivacaftor and ivacaftor) and Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor), but these treatments are not applied for those bearing nonsense mutations (Khor et al., 2022). Despite the relative success of symptomatic and pathological treatments, cystic fibrosis is incurable in most cases and patients must permanently take these costly drugs, which put significant financial stress on patients (Kondrateva et al., 2021a). The development of new approaches including iPSC-based gene therapy is becoming a highly hot issue now (Kondrateva et al., 2021a). The pluripotency and genomic profile of the iPSC cell lines have been validated as a resource that can be used for pharmacological investigations and drug screening associated with mutations of CFTR genes and provide hope for curing cystic fibrosis in the future (Merkert et al., 2020). Another advantage of iPSCs compared with small-molecular drugs is that the patient-specific iPSC cell lines carrying nonsense mutations could bring new therapeutic hope, including the development of personalized pathogenic therapy, pharmacological research, and precise medical drug screening for patients with extremely rare mutation types (Merkert et al., 2020). However, because iPSCs are obtained through gene reprogramming technology, there may be potential genetic mutations and epigenetic changes that may cause safety issues (Liu et al., 2018; Parrotta et al., 2020). Furthermore, the generation and identification of iPSC cell lines still require high costs, and the efficiency of reprogramming is generally low. Therefore, an economic and effective method for generating and differentiating iPSC is necessary for cell-based therapy and drug screening for personalized therapy.

Human iPSCs are characterized by human origin, pluripotency, and ultimate differentiation into any disease-related cell type, as well as epigenetic and genetic matching to the patients they have been derived from, which makes them a reliable avenue for organ fibrosis treatment. Human iPSCs are readily available, suitable for mass production, and stable at low temperatures without loss of function. Besides, iPSCs may eliminate ethical issues and religious concerns compared with ESCs. Moreover, human iPSCs may reduce the risk of immune rejection and be able to achieve personalized precision therapy by using patient-specific stem cells allowing for gene targeting and gene editing technology to correct mutations (Chun et al., 2011; Choi et al., 2013).

iPSC technology inevitably has some limitations associated with the reprogramming process: 1) Since iPSC is produced by retrovirus or lentivirus vectors, the genetic material introduced by retrovirus may be randomly integrated into the host genome, which may cause genetic abnormalities and teratoma (Singh et al., 2015). Recently, some of the safety problems concerning iPSC-based cell therapy and basic discovery have been partially resolved by using a no-integration virus, viral-free constructs, or even recombinant proteins. These methods make iPSCs safer and more suitable for clinical use (Okita et al., 2008; Stadtfeld et al., 2008; Yu et al., 2009; Zhou et al., 2009; Wysoczynski and Bolli, 2020). 2) The undifferentiated iPSCs have the risk for potential tumorigenicity. The iPSC under undifferentiated conditions may develop into teratoma and malignant tumors such as neuroblastoma and follicular carcinoma. There is also a risk of tumorigenesis after transplantation of contaminated iPSCs (Okita et al., 2008). The use of fluorescent-activated cell sorting or magnetic bead sorting purification can eliminate the potential tumorigenic risk to a certain extent (Sutermaster and Darling, 2019). 3) Reprogrammed cells may retain the epigenetic feature of the somatic cells where they originate, and the accumulation of chromosomal and/or mutations may display genomic instability (Liu et al., 2018; Parrotta et al., 2020). Therefore, before clinical application, these technologies should be tested in large animal models because they can predict human responses better than rodents (Harding et al., 2013; Nicolas et al., 2016). 4) More and more laboratories adopted iPSCs, however, only a small number of cells are eventually completely reprogrammed due to the inefficiency of reprogramming techniques, and there is heterogeneity among iPSC cells, therefore it is a big challenge to make every researcher under unified quality control (Scudellari, 2016). 5) Recent advances in gene-editing technologies, particularly CRISPR/Cas9, enable the rapid generation of disease models based on genetically defined human iPSC. But a major challenge in using the application of CRISPR/Cas9 technology is the possibility of off-target effects (Shi et al., 2017). Gene editing tools are also constantly being improved which may help to solve the problem of off-target effects. 6) Human iPSCs carry large amounts of private information (DNA), if abused, may violate the law and personal privacy. Despite the death of the donor, iPSCs still contain information about their close relatives, which may be an ethical and legal issue regarding personal privacy (Lin et al., 2004).

On the other hand, the limitations of iPSC reprogramming technology as mentioned above lead to similar deficiencies in iPSCs-derived cells. Furthermore, iPSCs-derived cells cannot be fully consistent with the phenotype and function of endogenous tissue-resident mature somatic cells (Zhang et al., 2009; Zhou et al., 2014; Toyohara et al., 2015; Choi et al., 2020; Tanaka et al., 2022). For example, previous studies have shown that even under standard two-dimensional culture conditions, after 8 weeks of iPSCs differentiation, the phenotype of mature cells derived from iPSCs is still in an embryonic state, but the 3D culture methodology can simulate the environment of mature somatic cell cells, which may promote cell differentiation and phenotype transformation to some extent (Zhang et al., 2009; Jacob et al., 2017). In addition, several studies reported that iPSCs-derived macrophages and monocyte-derived macrophages have similar phenotypes and functions. But the phenotype of iPSCs-derived macrophages is sometimes different from that of monocytes-derived macrophages or tissue-resident macrophages (Tanaka et al., 2022). Zhou et al. revealed that a limited number of undifferentiated iPSCs express alveolar epithelial markers during the culture process, indicating a lower efficiency of iPSC differentiation (Zhou et al., 2014). Besides, Toyohara et al. reported that the expression levels of some endothelial markers in human iPSCs-derived endothelial cells and natural human cardiac endothelial cells are different, which indicates that human iPSCs-derived endothelial cells may not be as mature and stable as mature somatic cells (Fan et al., 2022). However, the above limitations can be achieved by optimizing cell culture conditions and using ECM of normal mature somatic cell cells, which may improve the differentiation efficiency of iPSC and the ability to recapitulate the phenotype and function of mature somatic cell cells (Zhang et al., 2009; Chen et al., 2011).

Despite its functional role in the pathogenesis and treatment of fibrosis, the use of human iPSC-based cell therapy for organ fibrosis is still in the experimental stage after years of research. Problems include bioethical constraints, the safety of cell transplantation, routes of delivery, and the dose and timing of administration. Further studies are needed to establish the optimal strategy for the effective use of cell therapy for organ fibrosis (Ghadiri et al., 2016). Researchers must persevere and patiently conduct further research related to drug discovery based on iPSC. They will need strong support from the pharmaceutical industry and the government to advance cell therapy. The clinical application of iPSCs still has a long way to go.