1 Introduction Research on stem cells of adult or fetal origin in Iran has kindled hope for the possibility of reducing patient suffering and treatment for non‐remediable,chronic disorders. This hope has successfully encouraged patients to pursue rehabilitation protocols,in spite of them being lengthy and expensive,as these protocols need active participation by both the patient and the family. Meanwhile,important ethical concerns remain as the main hurdle. These concerns include patient safety and respect for the human fetus. Undoubtedly, longstanding benefits from such studies are dependent on adhering to these regulations and ethical concerns. The concerns described here are consistent with international knowledge as well as Islamic and Iranian culture. Additionally,a special consideration has been made,of the human health and ethical guidelines concerning tissue and cell handling as well as clinical trials. Every researcher or clinician who employs stem cells for the treatment of human disorders in Iran adheres to the letter and spirit of these guidelines. Additionally,he or she is also required to comply with both the general ethical guidelines of medical research and the special guidelines in research ethics depending on the subjects that are studied. However,certain other recommendations and regulations pertinent to the field of research in this regard also need to be considered.

2 Sources of cell harvest Cells may be harvested from redundant embryos generated during infertility treatment involving in vitro fertilization or from aborted fetuses. They may also be obtained from therapeutic and research cloning of the embryos. Pluripotent stem cells may be induced, or may be obtained from cord blood or newborn placentae. In case of living donors,cells for research purposes may be sourced only from renewable tissues that can be re‐substituted. These cells may be cultured either in autologous or recombinant serum. Isolated cells are recommended to be well identified by standard characterization tests. Autologous stem cells may be harvested for research and therapeutic purposes^[1].

3 Regulations for harvesting cells from embryos Embryos donated for the purpose of stem cell research are to be maintained in culture media and implantation in a human uterus or that of any other species is to be avoided. Ova,sperm,embryos,or any other forms of human tissue used for stem cell culture are not procured via conventional trading and business transactions,and a strong consent should exist before the study begins. Procurement of human embryos or gametes,via illegal means or illegal purchase of an embryo is not recommended and strongly discouraged. Free informed consent is required from both parents of the embryo,and in the case of a third party for gamete donation,his/her consent is also required,to allow use of the final embryo for research purposes. Specialist technicians responsible for harvesting embryos should be other than those involved in stem cell research. The decision for use of the embryo for stem cell culture should have no influence on the decision to abort,i.e.,those taking the decision of abortion should be different from those conducting stem cell researches. Ova to be used for stem cell culture should be those obtained from redundant embryos generated during infertility treatment. Healthy human embryos are not collected for research purposes,however,if an alternative method is not at hand or available,this method is acceptable in case of therapeutic purposes^[2].

4 Regulations for cell disposal Induced pluripotent stem cells are not to be donated directly to individuals,except for autologous (semi allograft) recipients,and are not to be mixed with human or non‐human embryos. Informed consent is required to be obtained from all subjects participating in research studies,with regard to each specific study^[3]. While obtaining the consent from donors of stem cells, all the pertinent information required for an informed decision is provided to the participants,including the intended use and chances of damage and necrosis of the donated tissue during stem cell extraction. The chances for long‐term preservation for future use are also discussed,if pertinent.

5 Stem cell manufacturing Advanced cellular therapy requires extensive validation, control,and documentation during manufacture and use. Accordingly,stem cells as advanced medicinal products are produced in compliance with current good manufacturing practice (cGMP) standards^[4] to ensure the safety,quality,and identity of cell products during translation from the bench to the bedside^[5].Accordingly,the Iranian Stem Cell Council recommended a national guideline on cell manufacturing to the Iranian Food and Drug Administration (Iranian FDA),which in turn,released regulations on human cell and gene therapy in 2015,based on this guideline.

6 Economic aspects of stem cell therapy The monetary benefits of the research program (present and future) are not passed on to the participants. Therapeutic and medical benefits of the research are not confined to the donor,rather,all of society could benefit from the results. Providing informed consent or refusing it does not affect the donor’s treatment. Additionally,after enrollment,the participant is free to withdraw from the program at any time and this decision will not affect his/her treatment course. In case of embryo donation,the donors are assured that the donated embryo will not be used for implantation in another couple. Donors are routinely screened for infectious and genetic disorders,since the donated cells may undergo genetic manipulation. To maintain confidentiality, personal information of the participants is not disclosed. The research centers use globally accepted codes to comply with secrecy. Once the project is complete or prematurely terminated for any reason,this information is discarded. No additional information,outside of that required for the program will be obtained,as it may jeopardize the protocol and ethical codes. Though there is a risk for commercialization of the donated cells,the donor is not permitted to do so^[6].

7 Regulations for animal modeling In vivo studies are needed to demonstrate the proofof‐ concept in animal models and also to predict potential concerns during clinical application. Therefore, clinical translation of cell‐based therapies is based on preclinical studies of feasibility,safety,and efficacy^[7]. In addition,preclinical studies establish the activity, effective dose,dosing regimen,and final route of administration of cell‐based products^[8]. Based on the stage of cell therapy,testing in different animal species is required^[7]. Ideally,these studies should simulate human disease pathogenesis and the intervention in animals would mimic the intended clinical application. The type,duration,and scope of preclinical studies depend on the nature and survival of the cell product. Additionally,limitations and differences between the animal model and human disease are determined before clinical application^[8].

Adequate preclinical animal studies are completed before moving on to the clinical phase of research. Small animal models are used for the following purposes: testing wild‐type,diseased,or genetically manipulated cells; evaluation of improvement after cell therapy; and assessment of biological mechanisms for tissue repair. Evaluation of dosage and route of cell delivery, effect of age,disease severity,and efficacy of cell therapies are performed in small animal models. Larger animal models are used in for studies where small animal models are inappropriate or in case of biomaterials such as bone,cartilage,tendon,etc.

Primate studies are conducted only when indispensable for data that is not possible to be obtained with other methods. These studies are preferably conducted by an expert veterinarian. As a final step before clinical trials,human stem cells are directly tested in animals.

8 Conclusion All cell therapy trials are required to strictly abide with the ethical codes,national and local regulations, and safety requirements,as well as consider human rights and respect. Adherence to these standards has facilitated the conduct of human cell therapy trials for research,academic advancement,and therapy.

Acknowledgements We are indebted to the kind and generous contribution of all the authors for their kind and senseful contributions to the preparation of the article.

Conflict of interests The authors have no financial interest to disclose regarding the article.