Transplantation Of Fetal Cells Research Articles

Embryonic vitamin D deficiency programs hematopoietic stem cells to induce type 2 diabetes

Environmental factors may alter the fetal genome to cause metabolic diseases. It is unknown whether embryonic immune cell programming impacts the risk of type 2 diabetes in later life. We demonstrate that transplantation of fetal hematopoietic stem cells (HSCs) made vitamin D deficient in utero induce diabetes in vitamin D-sufficient mice. Vitamin D deficiency epigenetically suppresses Jarid2 expression and activates the Mef2/PGC1a pathway in HSCs, which persists in recipient bone marrow, resulting in adipose macrophage infiltration. These macrophages secrete miR106-5p, which promotes adipose insulin resistance by repressing PIK3 catalytic and regulatory subunits and down-regulating AKT signaling. Vitamin D-deficient monocytes from human cord blood have comparable Jarid2/Mef2/PGC1a expression changes and secrete miR-106b-5p, causing adipocyte insulin resistance. These findings suggest that vitamin D deficiency during development has epigenetic consequences impacting the systemic metabolic milieu.

Assessment of the effect of cell transplantation on DNA repair in rat hepatocytes exposed to carbon tetrachloride (CCl4) by DNA comet assay

Introduction. The effect of carbon tetrachloride (freon-10, asordin, hladon-10) is an organochlorine compound with the chemical formula CCl4 and the subsequent transplantation of fetal liver cells (FLC) on DNA degradation and repair in rat hepatocytes by means of alkaline single-cell gel electrophoresis (DNA comet assay) was assessed. Material and methods. Acute toxic damage to the rat liver was simulated by a single oral administration to female Wistar rats of CCl4 in an oil solution at a dose of 3000 mg/kg. As a protective agent, a suspension of FLC of E19 rat fetuses was used. Quantitative assessment of the degree of damage to the nuclear DNA of liver cells was performed by DNA comet assay on days 1, 3, 5, 7 and 16 of the experiment. Results. Intravenous injections of fetal liver cells 6 h after exposure to CCl4 induces DNA repair processes in rat hepatocytes in 5-7 days and led to a decrease in the intensity of nuclear DNA damage. The trend toward a decrease in the number of undamaged hepatocytes continued on the 16th day of the experiment, and, therewith, the enhancement of reparative processes after FLC injection revealed itself in in a significant decrease in the number of hepatocytes with a high intensity of nuclear DNA damage. Limitations. To prevent unwanted death of animals in the group, studies were limited to a dose of 3000 mg/kg of CCl4 in oil solution. Conclusion. The method of alkaline single-cell gel electrophoresis (DNA comet assay) allowed quantitative assessment of the degrees of genome damage and repair. The obtained positive results suggest that FLC exert a protective effect of the structure of the DNA of rat liver role after acute exposure to CCl4.

Current Status and Future Perspectives on Stem Cell-Based Therapies for Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, affecting 1%-2% of the population over the age of 65. As the population ages, it is anticipated that the burden on society will significantly escalate. Although symptom reduction by currently available pharmacological and/or surgical treatments improves the quality of life of many PD patients, there are no treatments that can slow down, halt, or reverse disease progression. Because the loss of a specific cell type, midbrain dopamine neurons in the substantia nigra, is the main cause of motor dysfunction in PD, it is considered a promising target for cell replacement therapy. Indeed, numerous preclinical and clinical studies using fetal cell transplantation have provided proof of concept that cell replacement therapy may be a viable therapeutic approach for PD. However, the use of human fetal cells remains fraught with controversy due to fundamental ethical, practical, and clinical limitations. Groundbreaking work on human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells, coupled with extensive basic research in the stem cell field offers promising potential for hPSC-based cell replacement to become a realistic treatment regimen for PD once several major issues can be successfully addressed. In this review, we will discuss the prospects and challenges of hPSC-based cell therapy for PD.

Current Knowledge and Future Directions in Huntington’s Disease

Introduction: Huntington's Disease (HD) is a hereditary, neurodegenerative disorder due to abnormal repeats of the CAG triplet in the IT-15 gene. It is characterized by a triad of progressive motor, psychiatric and cognitive symptoms, resulting from striatal neuronal loss. The impact of HD in Latin America is evidenced by the prevalence rates in Maracaibo (Venezuela) and Juan de Acosta (Colombia), which are the highest recorded in the world. This contrasts with the social abandonment and the scarce intervention of local governments.
 Aim: Provide an approach to the most relevant aspects of HD from its pathogenesis and associated genetic polymorphisms, to the current treatment options.
 Methodology: A literature review was performed of the state of the art of prognosis and treatment strategies in HD, including the identification of different polymorphic markers in the genes coding for UCHL1, HIP1, PGC1α, GRIK2, TBP, BDNF, among others, and its associations in the evolution of the disease in the presence of abnormal CAG repeats.
 Conclusion: Even though in the last decades many researchers have focused on the development of curative treatment, there is no effective therapeutic target to prevent the clinical onset of the disease or to delay its progression. Instead, current pharmacological management is palliative, the evidence to generalize the surgical approaches is insufficient. Newly, the fetal neural cell transplantation into the striatum is offered as the surgical option that provides hope for the development of a true disease-modifying treatment.

Current Knowledge and Future Directions in Huntington’s Disease

Introduction: Huntington's Disease (HD) is a hereditary, neurodegenerative disorder due to abnormal repeats of the CAG triplet in the IT-15 gene. It is characterized by a triad of progressive motor, psychiatric and cognitive symptoms, resulting from striatal neuronal loss. The impact of HD in Latin America is evidenced by the prevalence rates in Maracaibo (Venezuela) and Juan de Acosta (Colombia), which are the highest recorded in the world. This contrasts with the social abandonment and the scarce intervention of local governments.
 Aim: Provide an approach to the most relevant aspects of HD from its pathogenesis and associated genetic polymorphisms, to the current treatment options.
 Methodology: A literature review was performed of the state of the art of prognosis and treatment strategies in HD, including the identification of different polymorphic markers in the genes coding for UCHL1, HIP1, PGC1α, GRIK2, TBP, BDNF, among others, and its associations in the evolution of the disease in the presence of abnormal CAG repeats.
 Conclusion: Even though in the last decades many researchers have focused on the development of curative treatment, there is no effective therapeutic target to prevent the clinical onset of the disease or to delay its progression. Instead, current pharmacological management is palliative, the evidence to generalize the surgical approaches is insufficient. Newly, the fetal neural cell transplantation into the striatum is offered as the surgical option that provides hope for the development of a true disease-modifying treatment.

Clinical Outcomes of Fetal Stem Cell Transplantation in Type 1 Diabetes Are Related to Alternations to Different Lymphocyte Populations.

Background: In patients with diabetes, transplantation of stem cells increases C-peptide levels and induces insulin independence for some period. Today, this positive therapeutic outcome is widely attributed to the well-documented immunomodulatory properties of stem cells. The aim of this study was to report alternations (the trend of increase or decrease) in different lymphocyte populations in a stem cell clinical trial performed in our institute. Methods: Recorded data of a clinical trial conducted on 72 patients with type 1 diabetes who had received fetal stem cell transplantation several years ago and were regularly monitored before and after the procedure in 1, 3, 6, 12, 24 months were analyzed. In these regular follow-up visits, insulin demand, HbA1c, C-peptide, and alternation to B cell and T cell populations were analyzed and recorded. For the purpose of the current study, patients were retrospectively divided into 2 groups, namely, those with the positive response to treatment and patients without such response. Temporary positive therapeutic response was defined by 2 different indicators, namely, plasma C-peptide levels and insulin dose-adjusted A1C (IDAA1c), which was calculated as A1C (percent) + (4 × insulin dose (units per kilogram per 24 h). Data analysis was performed by means of SPSS Version 18. Results: Besides the short-term therapeutic effect, we observed remarkably significant alternations to the populations of B and T lymphocytes in the recipients. When patients were retrospectively assigned to 2 different groups of patients with a positive therapeutic response (based on C-peptide changes) and those without it, it was observed that alternations to different populations of B-cells and T-cells were significantly different in these 2 groups. Conclusion: Our results demonstrated that transplantation of stem cells leads to significant positive therapeutic outcomes in one group of patients who showed totally distinct patterns of alternation to different groups of lymphocytes.

P.102: Long Term Outcomes After Fetal Pancreatic Stem Cell Transplantation in Diabetes Mellitus: Data From Unified National Electronic Health System 2014–2019

Introduction: Fetal pancreatic stem cell transplantations (FPCT) from the aborted fetuses of 16–20 weeks gestation have been approved for the treatment of diabetes mellitus (DM) in a single tertiary research and training hospital in Kazakhstan. Although the immediate short-term beneficial effect was observed, there was a lack of long-term mortality assessment and the risk of diabetes-related complications among patients receiving FPCT compared to patients receiving conventional treatment (CT). We aimed to study long-term all-cause mortality and diabetes-related complications in DM patients who underwent EPCT versus CT using large-scale administrative health data from Unified National Electronic Health System (UNEHS). Methods: The initial cohort of 102,611 patients who were admitted to the hospital with DM were identified using ICD-10 codes through UNEHS between 2014–2019. Out of them, 504 patients who underwent FPCT were defined using ICD-9 procedure codes. Mortality data and patient-related demographics were linked from the National Population Registry. Identified datasets were cross-checked with the whole UNEHS dataset (n=1,565,093 observations) to ascertain the following complications/comorbidities: coronary heart disease (CHD), stroke, retinopathy, nephropathy, neuropathy, diabetic foot, neoplasms. Based on patients’ baseline characteristics (age, sex, duration of DM, residency, ethnicity, number of hospitalizations, and type of diabetes), the cohort of FPCT patients (n=504) matched with a cohort of CT patients (n=102,611) with a 1:5 ratio by propensity score matching (PSM). The final cohort of 2847 patients (504 with EPCT vs 2,343 with CT) was further evaluated. Results: After PS matching, baseline characteristics for FPCT and CT groups did not differ. Median (IQR) age was 50.6 (41.5–57.4) years old and the median duration of diabetes accounted for 6.3 (4.7–10.7) years. The cohort consisted of 55.4% females, 75.2% Kazakhs, 85.3% of type 2 DM, and 72.2% of urban residents. The median number of hospitalizations in 2014–2019 was 3 (1–6). The results of diabetes-related events and all-cause mortality presented in table 1.In logistic regression analysis, FPCT group had 48% lower risk of all-cause death compared to CT group (Odds Ratio 0.52; 95%CI: 0.37–0.72; p-value <0.001). Also, those DM patients receiving FPCT compared to the CT group were less likely to experience CHD, diabetic retinopathy, neuropathy, and diabetic foot, however, they were more likely to have diabetic nephropathy. There was no difference between the groups in terms of stroke and cancer incidences. Survival analysis depicted in figure 1.Conclusion: Findings suggest that patients receiving FPCT had a 48% lower risk of all-cause death. We also reveal better outcomes for the FPCT group regarding CHD, retinopathy, nephropathy, neuropathy, and diabetic foot, however, the EPCT group had a higher risk of nephropathy. Further investigations involving clinical and laboratory data are warranted. This study was supported by grants from the Nazarbayev University Faculty Development Research Grant Program FDCRGP 2020–2022 (Funder Project Reference: 240919FD3913).

Transforming trash to treasure Cultural ambiguity in foetal cell research

BackgroundRich in different kind of potent cells, embryos are used in modern regenerative medicine and research. Neurobiologists today are pushing the boundaries for what can be done with embryos existing in the transitory margins of medicine. Therefore, there is a growing need to develop conceptual frameworks for interpreting the transformative cultural, biological and technical processes involving these aborted, donated and marginal embryos. This article is a contribution to this development of frameworks.MethodsThis article examines different emotional, cognitive and discursive strategies used by neurobiologists in a foetal cell transplantation trial in Parkinson’s disease research, using cells harvested from aborted embryos. Two interviews were analysed in the light of former observations in the processing laboratories, using the anthropologist Mary Douglas’s concept of pollution behaviour and the linguist, philosopher, psychoanalyst and feminist Julia Kristeva’s concept of the abjective to explain and make sense of the findings.ResultsThe findings indicate that the labour performed by the researchers in the trial work involves transforming the foetal material practically, as well as culturally, from trash to treasure. The transformation process contains different phases, and in the interview material we observed that the foetal material or cells were considered objects, subjects or rejected as abject by the researchers handling them, depending on what phase of process or practice they referred to or had experience of. As demonstrated in the analysis, it is the human origin of the cell that makes it abjective and activates pollution discourse, when the researchers talk of their practice.ConclusionsThe marginal and ambiguous status of the embryo that emerges in the accounts turns the scientists handling foetal cells into liminal characters in modern medicine. Focusing on how practical as well as emotional and cultural strategies and rationalizations of the researchers emerge in interview accounts, this study adds insights on the rationale of practically procuring, transforming and utilizing the foetal material to the already existing studies focused on the donations. We also discuss why the use and refinement of a tissue, around which there is practical consensus but cultural ambiguity, deserves further investigation.

GDNF to the rescue: GDNF delivery effects on motor neurons and nerves, and muscle re-innervation after peripheral nerve injuries.

Peripheral nerve injuries commonly occur due to trauma, like a traffic accident. Peripheral nerves get severed, causing motor neuron death and potential muscle atrophy. The current golden standard to treat peripheral nerve lesions, especially lesions with large (≥ 3 cm) nerve gaps, is the use of a nerve autograft or reimplantation in cases where nerve root avulsions occur. If not tended early, degeneration of motor neurons and loss of axon regeneration can occur, leading to loss of function. Although surgical procedures exist, patients often do not fully recover, and quality of life deteriorates. Peripheral nerves have limited regeneration, and it is usually mediated by Schwann cells and neurotrophic factors, like glial cell line-derived neurotrophic factor, as seen in Wallerian degeneration. Glial cell line-derived neurotrophic factor is a neurotrophic factor known to promote motor neuron survival and neurite outgrowth. Glial cell line-derived neurotrophic factor is upregulated in different forms of nerve injuries like axotomy, sciatic nerve crush, and compression, thus creating great interest to explore this protein as a potential treatment for peripheral nerve injuries. Exogenous glial cell line-derived neurotrophic factor has shown positive effects in regeneration and functional recovery when applied in experimental models of peripheral nerve injuries. In this review, we discuss the mechanism of repair provided by Schwann cells and upregulation of glial cell line-derived neurotrophic factor, the latest findings on the effects of glial cell line-derived neurotrophic factor in different types of peripheral nerve injuries, delivery systems, and complementary treatments (electrical muscle stimulation and exercise). Understanding and overcoming the challenges of proper timing and glial cell line-derived neurotrophic factor delivery is paramount to creating novel treatments to tend to peripheral nerve injuries to improve patients’ quality of life.

Industrial Development of Standardized Fetal Progenitor Cell Therapy for Tendon Regenerative Medicine: Preliminary Safety in Xenogeneic Transplantation.

Tendon defects require multimodal therapeutic management over extensive periods and incur high collateral burden with frequent functional losses. Specific cell therapies have recently been developed in parallel to surgical techniques for managing acute and degenerative tendon tissue affections, to optimally stimulate resurgence of structure and function. Cultured primary human fetal progenitor tenocytes (hFPT) have been preliminarily considered for allogeneic homologous cell therapies, and have been characterized as stable, consistent, and sustainable cell sources in vitro. Herein, optimized therapeutic cell sourcing from a single organ donation, industrial transposition of multi-tiered progenitor cell banking, and preliminary preclinical safety of an established hFPT cell source (i.e., FE002-Ten cell type) were investigated. Results underlined high robustness of FE002-Ten hFPTs and suitability for sustainable manufacturing upscaling within optimized biobanking workflows. Absence of toxicity or tumorigenicity of hFPTs was demonstrated in ovo and in vitro, respectively. Furthermore, a 6-week pilot good laboratory practice (GLP) safety study using a rabbit patellar tendon partial-thickness defect model preliminarily confirmed preclinical safety of hFPT-based standardized transplants, wherein no immune reactions, product rejection, or tumour formation were observed. Such results strengthen the rationale of the multimodal Swiss fetal progenitor cell transplantation program and prompt further investigation around such cell sources in preclinical and clinical settings for musculoskeletal regenerative medicine.

Treatments Being Developed in Retinitis Pigmentosa

Recent developments in understanding the pathophysiology of retinitis pigmentosa (RP) have shown that there have been new hopes in the treatment of this disease which can cause severe vision loss. Proven therapy for RP-associated photoreceptor loss and retinal pigment epithelial damage has not yet been reported. New or experimental approaches for the treatment of RP include platelet-rich plasma, gene therapy, transplantation of fetal retinal cells or stem cells, and electronic retinal prostheses.

Retrospective Evaluation of Progenitor Biological Bandage Use: A Complementary and Safe Therapeutic Management Option for Prevention of Hypertrophic Scarring in Pediatric Burn Care

Progenitor Biological Bandages (PBB) have been continuously applied clinically in the Lausanne Burn Center for over two decades. Vast translational experience and hindsight have been gathered, specifically for cutaneous healing promotion of donor-site grafts and second-degree pediatric burns. PBBs constitute combined Advanced Therapy Medicinal Products, containing viable cultured allogeneic fetal dermal progenitor fibroblasts. Such constructs may partly favor repair and regeneration of functional cutaneous tissues by releasing cytokines and growth factors, potentially negating the need for subsequent skin grafting, while reducing the formation of hypertrophic scar tissues. This retrospective case-control study (2010–2018) of pediatric second-degree burn patients comprehensively compared two initial wound treatment options (i.e., PBBs versus Aquacel® Ag, applied during ten to twelve days post-trauma). Results confirmed clinical safety of PBBs with regard to morbidity, mortality, and overall complications. No difference was detected between groups for length of hospitalization or initial relative burn surface decreasing rates. Nevertheless, a trend was observed in younger patients treated with PBBs, requiring fewer corrective interventions or subsequent skin grafting. Importantly, significant improvements were observed in the PBB group regarding hypertrophic scarring (i.e., reduced number of scar complications and related corrective interventions). Such results establish evidence of clinical benefits yielded by the Swiss fetal progenitor cell transplantation program and favor further implementation of specific cell therapies in highly specialized regenerative medicine.

Generation of reconstituted hemato-lymphoid murine embryos by placental transplantation into embryos lacking HSCs

In order to increase the contribution of donor HSC cells, irradiation and DNA alkylating agents have been commonly used as experimental methods to eliminate HSCs for adult mice. But a technique of HSC deletion for mouse embryo for increase contribution of donor cells has not been published. Here, we established for the first time a procedure for placental HSC transplantation into E11.5 Runx1-deficient mice mated with G1-HRD-Runx1 transgenic mice (Runx1-/-::Tg mice) that have no HSCs in the fetal liver. Following the transplantation of fetal liver cells from mice (allogeneic) or rats (xenogeneic), high donor cell chimerism was observed in Runx1-/-::Tg embryos. Furthermore, chimerism analysis and colony assay data showed that donor fetal liver hematopoietic cells contributed to both white blood cells and red blood cells. Moreover, secondary transplantation into adult recipient mice indicated that the HSCs in rescued Runx1-/-::Tg embryos had normal abilities. These results suggest that mice lacking fetal liver HSCs are a powerful tool for hematopoiesis reconstruction during the embryonic stage and can potentially be used in basic research on HSCs or xenograft models.

Clinical Trial for Parkinson's Disease Gets a Green Light in the US.

Cell-based therapy is expected as an alternative treatment for Parkinson's disease. In this issue of Cell Stem Cell, two accompanying papers (Kim etal., 2021; Piao etal., 2021) report the induction of clinically applicable dopaminergic neurons from human embryonic stem cells and the results of pre-clinical study toward a clinical trial.

Assessment of immune-alternations and their correlations with therapeutic outcomes of transplantation of autologous Mesenchymal and Allogenic fetal stem cells in patients with type 1 diabetes: a study protocol.

Stem-cell therapy, which has recently emerged as a potentially therapeutic option for diabetes, is demonstrated to significantly alter both cellular and non-cellular elements of the immune system. In addition, it is demonstrated that allogenic stem-cells, once considered immune-privileged, can be rejected by the host immune system almost similar to any other somatic cell. To date, nonetheless, details of these intricate interactions remain obscure. The current study is designed to illuminate both aforementioned favorable and unfavorable stem cell-mediated immune reactions. Findings of this study may shed some light on how stem cells may exert their therapeutic effect in type 1 diabetes through immune system-mediated mechanisms and illuminate the partially-obscure immune-caused rejection of these cells. For the purpose of this study, frozen whole blood samples obtained from patients with type 1 diabetes who received stem cells at the Endocrinology and Metabolism Research Institute of Tehran University of Medical Sciences in two different clinical trials will be thawed and analyzed. These clinical trials were carried out using two different sources of stem cells, namely allogenic fetal and autologous mesenchymal cells. The samples we aim to analyze were obtained from the patients before the procedure and regularly after it, one, three, six, 12, and 24months later. For the purpose of this study, the following parameters will be measured: C-peptide levels, IDAA1c (a surrogate marker of beta cell function which is calculated as HbA1c (%) + [4 × insulin dose (units per kilogram per day)]), frequencies of islet-specific autoreactive CD8+ T cells (CTL), different lymphocyte subsets, thymic function indicators, T cell repertoire diversity (including Treg/Tconv ratios), plasma levels of several pro- and anti-inflammatory cytokines, diabetes autoantibodies, and HLA typing. The stem cell transplantation clinical trials which provided the primary source of our samples were carried out at the Endocrinology and Metabolism Research Institute of Tehran University of Medical Sciences between 2008 and 2012. These series of clinical trials have secured approval of the ethics committee of Tehran University of Medical Sciences (ethical code number: E-0089) and registered on the national clinical trial registry of Islamic Republic of Iran (IRCT) with the identifier codes: IRCT138810271414N8 (for autologous mesenchymal cells) and IRCT201103171414N23 (for allogenic fetal cells). Our findings are to be presented at international scientific events, published in peer-reviewed journals, and disseminated both electronically and in print. Besides, results of the current study will be used for design and implementation of future laboratory investigations and clinical trials at the Endocrinology and Metabolism Research Institute of Tehran University of Medical Sciences.

Effect of Transplantation of Neural Stem and Progenitor Cells on Memory in Animals with Alzheimer's Type Neurodegeneration.

The effects of systemic and intracerebral transplantation of human fetal neural stem and progenitor cells were studied on the model of olfactory bulbectomy in mice with developing signs of sporadic Alzheimer's disease. It was found that transplantation of these cells at certain stages of disease development contributed to improvement of spatial memory and preservation of hippocampal neurons in these animals.

Co-Existence of tau and α-synuclein pathology in fetal graft tissue at autopsy: A case report

IntroductionTransplant of fetal ventral mesencephalic tissue into the striatum of Parkinson's disease (PD) patients has been performed to increase dopamine production and stimulate neuronal regeneration. Analysis of fetal graft tissue at autopsy has demonstrated 6 cases of α-synuclein pathology in PD patients, one case with both α-synuclein and tau pathology in a PD patient, and two cases of tau pathology within a Huntington's Disease patient. MethodsA 49 year old man with PD underwent bilateral fetal ventral mesencephalic cell transplants into the striatum. Autopsy at age 70 included immunohistochemical staining of host and graft tissue with antibodies to phosphorylated α-synuclein and phosphorylated tau protein. ResultsAutopsy confirmed the diagnosis of PD. Immunohistochemical staining of graft tissue demonstrated frequent neuronal perikaryal inclusions of phosphorylated α -synuclein and tau in the left graft only. ConclusionSpeculations on the formation of pathology include: 1) α-synuclein and tau pathology spread from host to the graft in a neuron-neuron manner. 2) The nature of the fetal cells themselves, or transplantation process, may render fetal tissue more susceptible to the spontaneous generation of pathology. 3) Factors within host environment caused native tau and α-synuclein in fetal tissue graft to become phosphorylated.

The future of stem cell therapies for Parkinson disease.

Cell-replacement therapies have long been an attractive prospect for treating Parkinson disease. However, the outcomes of fetal tissue-derived cell transplants in individuals with Parkinson disease have been variable, in part owing to the limitations of fetal tissue as a cell source, relating to its availability and the lack of possibility for standardization and to variation in methods. Advances in developmental and stem cell biology have allowed the development of cell-replacement therapies that comprise dopamine neurons derived from human pluripotent stem cells, which have several advantages over fetal cell-derived therapies. In this Review, we critically assess the potential trajectory of this line of translational and clinical research and address its possibilities and current limitations and the broader range of Parkinson disease features that dopamine cell replacement based on generating neurons from human pluripotent stem cells could effectively treat in the future.

Multi-lineage Lung Regeneration by Stem Cell Transplantation across Major Genetic Barriers

Induction of lung regeneration by transplantation of lung progenitor cells is a critical preclinical challenge. Recently, we demonstrated that robust lung regeneration can be achieved if the endogenous stem cell niches in the recipient's lung are vacated by sub-lethal pre-conditioning. However, overcoming MHC barriers is an additional requirement for clinical application of this attractive approach. We demonstrate here that durable tolerance toward mis-matched lung progenitors and their derivatives can be achieved without any chronic immune suppression, by virtue of co-transplantation with hematopoietic progenitors from the same donor. Initial proof of concept of this approach was attained by transplantation of fetal lung cells comprising both hematopoietic and non-hematopoietic progenitors. Furthermore, an even higher rate of blood and epithelial lung chimerism was attained by using adult lung cells supplemented with bone marrow hematopoietic progenitors. These results lay the foundation for repair of lung injury through a procedure akin to bone marrow transplantation.

Swiss Fetal Transplantation Program and Non-enzymatically Isolated Primary Progenitor Cell Types for Regenerative Medicine.

Primary progenitor cell types adequately isolated from fetal tissue samples present considerable therapeutic potential for a wide range of applications within allogeneic musculoskeletal regenerative medicine. Progenitor cells are inherently differentiated and extremely stable in standard bioprocessing conditions and can be culture-expanded to establish extensive and robust cryopreserved cell banks. Stringent processing conditions and exhaustive traceability are prerequisites for establishing a cell source admissible for further cGMP biobanking and clinical-grade production lot manufacture. Transplantation programs are ideal platforms for the establishment of primary progenitor cell sources to be used for manufacture of cell therapies or cell-based products. Well-defined and regulated procurement and processing of fetal biopsies after voluntary pregnancy interruptions ensure traceability and safety of progeny materials and therapeutic products derived therefrom. We describe herein the workflows and specifications devised under the Swiss Fetal Progenitor Cell Transplantation Program in order to traceably isolate primary progenitor cell types in vitro and to constitute Parental Cell Banks fit for subsequent industrial-scale cGMP processing. When properly devised, derived, and maintained, such cell sources established after a single organ donation can furnish sufficient progeny materials for years of development in translational musculoskeletal regenerative medicine.