Transplantation of vascular endothelial growth factor-modified neural stem/progenitor cells promotes the recovery of neurological function following hypoxic-ischemic brain damage

Neural stem/progenitor cell （NSC） transplantation has been shown to effectively improve neurological function in rats with hypoxic-isch- emic brain damage. Vascular endothelial growth factor （VEGF） is a signaling protein that stimulates angiogenesis and improves neural regeneration. We hypothesized that transplantation of VEGF-transfected NSCs would alleviate hypoxic-ischemic brain damage in neo- natal rats. We produced and transfected a recombinant lentiviral vector containing the VEGF165gene into cultured NSCs. The transfected NSCs were transplanted into the left sensorimotor cortex of rats 3 days after hypoxic-ischemic brain damage. Compared with the NSCs group, VEGF mRNA and protein expression levels were increased in the transgene NSCs group, and learning and memory abilities were significantly improved at 30 days. Furthermore, histopathological changes were alleviated in these animals. Our findings indicate that transplantation of VEGF-transfected NSCs may facilitate the recovery of neurological function, and that its therapeutic effectiveness is better than that of unmodified NSCs.

Transcriptional regulation of adult neural stem/progenitor cells: tales from the subventricular zone

In rodents,well characterized neurogenic niches of the adult brain,such as the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampus,support the maintenance of neural/stem progenitor cells(NSPCs)and the production of new neurons throughout the lifespan.The adult neurogenic process is dependent on the intrinsic gene expression signatures of NSPCs that make them competent for self-renewal and neuronal differentiation.At the same time,it is receptive to regulation by various extracellular signals that allow the modulation of neuronal production and integration into brain circuitries by various physiological stimuli.A drawback of this plasticity is the sensitivity of adult neurogenesis to alterations of the niche environment that can occur due to aging,injury or disease.At the core of the molecular mechanisms regulating neurogenesis,several transcription factors have been identified that maintain NSPC identity and mediate NSPC response to extrinsic cues.Here,we focus on REST,Egr1 and Dbx2 and their roles in adult neurogenesis,especially in the subventricular zone.We review recent work from our and other laboratories implicating these transcription factors in the control of NSPC proliferation and differentiation and in the response of NSPCs to extrinsic influences from the niche.We also discuss how their altered regulation may affect the neurogenic process in the aged and in the diseased brain.Finally,we highlight key open questions that need to be addressed to foster our understanding of the transcriptional mechanisms controlling adult neurogenesis.

Perspectives on mesenchymal stem/progenitor cells and their derivates as potential therapies for lung damage caused by COVID-19

The new coronavirus,severe acute respiratory syndrome coronavirus-2(SARSCoV-2),which emerged in December 2019 in Wuhan,China,has reached worldwide pandemic proportions,causing coronavirus disease 2019(COVID-19).The clinical manifestations of COVID-19 vary from an asymptomatic disease course to clinical symptoms of acute respiratory distress syndrome and severe pneumonia.The lungs are the primary organ affected by SARS-CoV-2,with a very slow turnover for renewal.SARS-CoV-2 enters the lungs via angiotensinconverting enzyme 2 receptors and induces an immune response with the accumulation of immunocompetent cells,causing a cytokine storm,which leads to target organ injury and subsequent dysfunction.To date,there is no effective antiviral therapy for COVID-19 patients,and therapeutic strategies are based on experience treating previously recognized coronaviruses.In search of new treatment modalities of COVID-19,cell-based therapy with mesenchymal stem cells(MSCs)and/or their secretome,such as soluble bioactive factors and extracellular vesicles,is considered supportive therapy for critically ill patients.Multipotent MSCs are able to differentiate into different types of cells of mesenchymal origin,including alveolar epithelial cells,lung epithelial cells,and vascular endothelial cells,which are severely damaged in the course of COVID-19 disease.Moreover,MSCs secrete a variety of bioactive factors that can be applied for respiratory tract regeneration in COVID-19 patients thanks to their trophic,anti-inflammatory,immunomodulatory,anti-apoptotic,pro-regenerative,and proangiogenic properties.

Ultrastructure of human neural stem/progenitor cells and neurospheres

BACKGROUND： Biological and morphological characteristics of neural stem/progenitor cells （NSPCs） have been widely investigated. OBJECTIVE： To explore the ultrastructure of human embryo-derived NSPCs and neurospheres cultivated in vitro using electron microscopy. DESIGN, TIME AND SETTING： A cell biology experiment was performed at the Brain Tumor Laboratory of Soochow University, and Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University between August 2007 and April 2008. MATERIALS： Human fetal brain tissue was obtained from an 8-week-old aborted fetus; serum-free Dulbecco＇s modified Eagle＇s medium/F12 culture medium was provided by Gibco, USA; scanning electron microscope was provided by Hitachi Instruments, Japan; transmission electron microscope was provided by JEOL, Japan. METHODS： NSPCs were isolated from human fetal brain tissue and cultivated in serum-free Dulbecco＇s modified Eagle＇s medium/F12 culture medium. Cells were passaged every 5-7 days. After three passages, NSPCs were harvested and used for ultrastructural examination. MAIN OUTCOME MEASURES： Ultrastructural examination of human NSPCs and adjacent cells in neurospheres. RESULTS： Individual NSPCs were visible as spherical morphologies with rough surfaces under scanning electron microscope. Generally, they had large nuclei and little cytoplasm. Nuclei were frequently globular with large amounts of euchromatin and a small quantity of heterochromatin, and most NSPCs had only one nucleolus. The Golgi apparatus and endoplasmic reticulum were underdeveloped; however, autophagosomes were clearly visible. The neurospheres were made up of NSPCs and non-fixiform material inside. Between adjacent cells and at the cytoplasmic surface of apposed plasma membranes, there were vesicle-like structures. Some membrane boundaries with high permeabilities were observed between some contiguous NSPCs in neurospheres, possibly attributable to plasmalemmal fusion between adjacent cells. CONCLUSION： A large number of autophagosomes were observed in NSPCs and gap junctions were visible between adjacent NSPCs.

PRELIMINARY STUDY OF RETROVIRAL MEDIATED TRANSFER OF THE HUMAN mdr-1 GENE INTO MURINE AND HUMAN HEMATOPOIETIC STEM/PROGENITOR CELLS

To investigate the characteristics of multidrugresistance and transplantation of modified stem/ progenitor cells by multidrugresistant gene (mdr1 gene), we established PA317/MDR1 cell line which producing retroviruses by transfecting the retroviral vector PHaMDR1/A into packging cell line PA317 by Lipofectin. The virus titer of the supernatants was 1.2×105 cfu/ml. We transfected the murine hematopietic cells collected from 5FU pretreated mice and they showed the ability to reconstitute the longterm hematopoiesis of preirradiated mice. After 4 months, both of bone marrow cells and peripheral blood cells of transplanted mice still contained mdr1 gene. We also transfered mdr1 gene into human bone marrow CD34+ cells selected by using magnetic cell sorting system. PCR analysis showed that transduced CD34+ cells maintained the mdr1 cDNA. A fraction of CFUGM originated from transfected CD34+ cells had the charactor of resistance to Taxol. It is indicated that mdr1 gene can be transduced into murine and human stem/proginitor cells through retroviral mediated gene transfer and it protects the transfected cells from cytotoxic drugs.

Human liver stem/progenitor cells decrease serum bilirubin in hyperbilirubinemic Gunn rat

AIM: To test the ability of adult-derived human liver stem/progenitor cells (ADHLSC) from large scale cultures to conjugate bilirubin in vitro and in bilirubin conjugation deficient rat.

Advanced glycation end productions and tendon stem/progenitor cells in pathogenesis of diabetic tendinopathy

Tendinopathy is a challenging complication observed in patients with diabetes mellitus.Tendinopathy usually leads to chronic pain,limited joint motion,and even ruptured tendons.Imaging and histological analyses have revealed pathological changes in various tendons of patients with diabetes,including disorganized arrangement of collagen fibers,microtears,calcium nodules,and advanced glycation end product(AGE)deposition.Tendon-derived stem/progenitor cells(TSPCs)were found to maintain hemostasis and to participate in the reversal of tendinopathy.We also discovered the aberrant osteochondrogenesis of TSPCs in vitro.However,the relationship between AGEs and TSPCs in diabetic tendinopathy and the underlying mechanism remain unclear.In this review,we summarize the current findings in this field and hypothesize that AGEs could alter the properties of tendons in patients with diabetes by regulating the proliferation and differentiation of TSPCs in vivo.

Propofol and remifentanil at moderate and high concentrations affect proliferation and differentiation of neural stem/progenitor cells

Propofol and remifentanil alter intracellular Ca^2＋ concentration （[Ca^2＋]i） in neural stem/progen-itor cells by activating γ-aminobutyric acid type A receptors and by reducing testosterone levels. However, whether this process affects neural stem/progenitor cell proliferation and differenti-ation remains unknown. In the present study, we applied propofol and remifentanil, alone or in combination, at low, moderate or high concentrations （1, 2–2.5 and 4–5 times the clinically effective blood drug concentration）, to neural stem/progenitor cells from the hippocampi of newborn rat pups. Low concentrations of propofol, remifentanil or both had no noticeable effect on cell proliferation or differentiation; however, moderate and high concentrations of propofol and/or remifentanil markedly suppressed neural stem/progenitor cell proliferation and differen-tiation, and induced a decrease in [Ca^2＋]i during the initial stage of neural stem/progenitor cell differentiation. We therefore propose that propofol and remifentanil interfere with the prolifer-ation and differentiation of neural stem/progenitor cells by altering [Ca^2＋]i. Our ifndings suggest that propofol and/or remifentanil should be used with caution in pediatric anesthesia.

Similarities and differences between mesenchymal stem/progenitor cells derived from various human tissues

BACKGROUND Mesenchymal stromal/stem cells (MSCs) constitute a promising tool in regenerative medicine and can be isolated from different human tissues. However, their biological properties are still not fully characterized. Whereas MSCs from different tissue exhibit many common characteristics, their biological activity and some markers are different and depend on their tissue of origin. Understanding the factors that underlie MSC biology should constitute important points for consideration for researchers interested in clinical MSC application. AIM To characterize the biological activity of MSCs during longterm culture isolated from: bone marrow (BM-MSCs), adipose tissue (AT-MSCs), skeletal muscles (SMMSCs), and skin (SK-MSCs). METHODS MSCs were isolated from the tissues, cultured for 10 passages, and assessed for: phenotype with immunofluorescence and flow cytometry, multipotency with differentiation capacity for osteo-, chondro-, and adipogenesis, stemness markers with qPCR for mRNA for Sox2 and Oct4, and genetic stability for p53 and c-Myc;27 bioactive factors were screened using the multiplex ELISA array, and spontaneous fusion involving a co-culture of SM-MSCs with BM-MSCs or AT-MSCs stained with PKH26 (red) or PKH67 (green) was performed. RESULTS All MSCs showed the basic MSC phenotype;however, their expression decreased during the follow-up period, as confirmed by fluorescence intensity. The examined MSCs express CD146 marker associated with proangiogenic properties;however their expression decreased in AT-MSCs and SM-MSCs, but was maintained in BM-MSCs. In contrast, in SK-MSCs CD146 expression increased in late passages. All MSCs, except BM-MSCs, expressed PW1, a marker associated with differentiation capacity and apoptosis. BM-MSCs and AT-MSCs expressed stemness markers Sox2 and Oct4 in long-term culture. All MSCs showed a stable p53 and c-Myc expression. BM-MSCs and AT-MSCs maintained their differentiation capacity during the follow-up period. In contrast, SK-MSCs and SM-MSCs had a limited ability to differentiate into adipocytes. BM-MSCs and AT-MSCs revealed similarities in phenotype maintenance, capacity for multilineage differentiation, and secretion of bioactive factors. Because AT-MSCs fused with SM-MSCs as effectively as BM-MSCs, AT-MSCs may constitute an alternative source for BM-MSCs. CONCLUSION Long-term culture affects the biological activity of MSCs obtained from various tissues. The source of MSCs and number of passages are important considerations in regenerative medicine.

Stages based molecular mechanisms for generating cholangiocytes from liver stem/progenitor cells

Except for the most organized mature hepatocytes,liver stem/progenitor cells(LSPCs)can differentiate into many other types of cells in the liver including cholangiocytes.In addition,LSPCs are demonstrated to be able to give birth to other kinds of extra-hepatic cell types such as insulin-producing cells.Even more,under some bad conditions,these LSPCs could generate liver cancer stem like cells(LCSCs)through malignant transformation.In this review,we mainly concentrate on the molecular mechanisms for controlling cell fates of LSPCs,especially differentiation of cholangiocytes,insulin-producing cells and LCSCs.First of all,to certificate the cell fates of LSPCs,the following three features need to be taken into account to perform accurate phenotyping:(1)morphological properties;(2)specific markers;and(3)functional assessment including in vivo transplantation.Secondly,to promote LSPCs differentiation,systematical attention should be paid to inductive materials(such as growth factors and chemical stimulators),progressive materials including intracellular and extracellular signaling pathways,and implementary materials(such as liver enriched transcriptive factors).Accordingly,some recommendations were proposed to standardize,optimize,and enrich the effective production of cholangiocyte-like cells out of LSPCs.At the end,the potential regulating mechanisms for generation of cholangiocytes by LSPCs were carefully analyzed.The differentiation of LSPCs is a gradually progressing process,which consists of three main steps:initiation,progression and accomplishment.It’s the unbalanced distribution of affecting materials in each step decides the cell fates of LSPCs.

Urine-derived stem/progenitor cells:A focus on their characterization and potential

Cell therapy,i.e.,the use of cells to repair an affected tissue or organ,is at the forefront of regenerative and personalized medicine.Among the multiple cell types that have been used for this purpose[including adult stem cells such as mesenchymal stem cells or pluripotent stem cells],urine-derived stem cells(USCs)have aroused interest in the past years.USCs display classical features of mesenchymal stem cells such as differentiation capacity and immunomodulation.Importantly,they have the main advantage of being isolable from one sample of voided urine with a cheap and unpainful procedure,which is broadly applicable,whereas most adult stem cell types require invasive procedure.Moreover,USCs can be differentiated into renal cell types.This is of high interest for renal cell therapy-based regenerative approaches.This review will firstly describe the isolation and characterization of USCs.We will specifically present USC phenotype,which is not an object of consensus in the literature,as well as detail their differentiation capacity.In the second part of this review,we will present and discuss the main applications of USCs.These include use as a substrate to generate human induced pluripotent stem cells,but we will deeply focus on the use of USCs for cell therapy approaches with a detailed analysis depending on the targeted organ or system.Importantly,we will also focus on the applications that rely on the use of USC-derived products such as microvesicles including exosomes,which is a strategy being increasingly employed.In the last section,we will discuss the remaining barriers and challenges in the field of USC-based regenerative medicine.

Stem/progenitor cells and obstructive sleep apnea syndrome - new insights for clinical applications

Obstructive sleep apnea syndrome(OSAS) is a widespread disorder, characterized by recurrent upper airway obstruction during sleep, mostly as a result of complete or partial pharyngeal obstruction. Due to the occurrence of frequent and regular hypoxic events, patients with OSAS are at increased risk of cardiovascular disease, stroke, metabolic disorders, occupational errors, motor vehicle accidents and even death. Thus, OSAS has severe consequences and represents a significant economic burden. However, some of the consequences, as well as their costs can be reduced with appropriate detection and treatment. In this context, the recent advances that were made in stem cell biology knowledge and stem cell- based technologies hold a great promise for various medical conditions, including respiratory diseases. However, the investigation of the role of stem cells in OSAS is still recent and rather limited, requiring further studies, both in animal models and humans. The goal of this review is to summarize the current state of knowledge regarding both lung resident as well as circulating stem/progenitor cells and discuss existing controversies in the field in order to identify future research directions for clinical applications in OSAS. Also, the paper highlights the requisite for inter-institutional, multi-disciplinary research collaborations in order to achieve breakthrough results in the field.

Profile of biological characterizations and clinical application of corneal stem/progenitor cells

Corneal stem/progenitor cells are typical adult stem/progenitor cells.The human cornea covers the front of the eyeball,which protects the eye from the outside environment while allowing vision.The location and function demand the cornea to maintain its transparency and to continuously renew its epithelial surface by replacing injured or aged cells through a rapid turnover process in which corneal stem/progenitor cells play an important role.Corneal stem/progenitor cells include mainly corneal epithelial stem cells,corneal endothelial cell progenitors and corneal stromal stem cells.Since the discovery of corneal epithelial stem cells(also known as limbal stem cells)in 1971,an increasing number of markers for corneal stem/progenitor cells have been proposed,but there is no consensus regarding the definitive markers for them.Therefore,the identification,isolation and cultivation of these cells remain challenging without a unified approach.In this review,we systematically introduce the profile of biological characterizations,such as anatomy,characteristics,isolation,cultivation and molecular markers,and clinical applications of the three categories of corneal stem/progenitor cells.

Rapamycin induces differentiation of glioma stem/progenitor cells by activating autophagy

Glioma stem/progenitor cells(GSPCs) are considered to be responsible for the initiation,propagation,and recurrence of gliomas.The factors determining their differentiation remain poorly defined.Accumulating evidences indicate that alterations in autophagy may influence cell fate during mammalian development and differentiation.Here,we investigated the role of autophagy in GSPC differentiation.SU-2 cells were treated with rapamycin,3-methyladenine(3-MA) plus rapamycin,E64d plus rapamycin,or untreated as control.SU-2 cell xenografts in nude mice were treated with rapamycin or 3-MA plus rapamycin,or untreated as control.Western blotting and immunocytochemistry showed up-regulation of microtubule-associated protein light chain-3(LC3)-II in rapamycin-treated cells.The neurosphere formation rate and the number of cells in each neurosphere were significantly lower in the rapamycin treatment group than in other groups.Real-time PCR and immunocytochemistry showed down-regulation of stem/progenitor cell markers and up-regulation of differentiation markers in rapamycin-treated cells.Transmission electron microscopy revealed autophagy activation in rapamycin-treated tumor cells in mice.Immunohistochemistry revealed decreased Nestin-positive cells and increased GFAP-positive cells in rapamycin-treated tumor sections.These results indicate that rapamycin induces differentiation of GSPCs by activating autophagy.

Why stem/progenitor cells lose their regenerative potential

Nowadays,it is clear that adult stem cells,also called as tissue stem cells,play a central role to repair and maintain the tissue in which they reside by their selfrenewal ability and capacity of differentiating into distinct and specialized cells.As stem cells age,their renewal ability declines and their capacity to maintain organ homeostasis and regeneration is impaired.From a molecular perspective,these changes in stem cells properties can be due to several types of cell intrinsic injury and DNA aberrant alteration(i.e epigenomic profile)as well as changes in the tissue microenviroment,both into the niche and by systemic circulating factors.Strikingly,it has been suggested that aging-induced deterioration of stem cell functions may play a key role in the pathophysiology of the various agingassociated disorders.Therefore,understanding how resident stem cell age and affects near and distant tissues is fundamental.Here,we examine the current knowledge about aging mechanisms in several kinds of adult stem cells under physiological and pathological conditions and the principal aging-related changes in number,function and phenotype that determine the loss of tissue renewal properties.Furthermore,we examine the possible cell rejuvenation strategies.Stem cell rejuvenation may reverse the aging phenotype and the discovery of effective methods for inducing and differentiating pluripotent stem cells for cell replacement therapies could open up new possibilities for treating age-related diseases.

Hypoxic pre-conditioned adipose-derived stem/progenitor cells embedded in fibrin conduits promote peripheral nerve regeneration in a sciatic nerve graft model

Recent results emphasize the supportive effects of adipose-derived multipotent stem/progenitor cells(ADSPCs)in peripheral nerve recovery.Cultivation under hypoxia is considered to enhance the release of the regenerative potential of ADSPCs.This study aimed to examine whether peripheral nerve regeneration in a rat model of autologous sciatic nerve graft benefits from an additional custom-made fibrin conduit seeded with hypoxic pre-conditioned(2%oxygen for 72 hours)autologous ADSPCs(n=9).This treatment mode was compared with three others:fibrin conduit seeded with ADSPCs cultivated under normoxic conditions(n=9);non-cell-carrying conduit(n=9);and nerve autograft only(n=9).A 16-week follow-up included functional testing(sciatic functional index and static sciatic index)as well as postmortem muscle mass analyses and morphometric nerve evaluations(histology,g-ratio,axon density,and diameter).At 8 weeks,the hypoxic pre-conditioned group achieved significantly higher sciatic functional index/static sciatic index scores than the other three groups,indicating faster functional regeneration.Furthermore,histologic evaluation showed significantly increased axon outgrowth/branching,axon density,remyelination,and a reduced relative connective tissue area.Hypoxic pre-conditioned ADSPCs seeded in fibrin conduits are a promising adjunct to current nerve autografts.Further studies are needed to understand the underlying cellular mechanism and to investigate a potential application in clinical practice.

Involvement of VLA-5 and VLA-6 in facilitating endothelium-oriented transmigration of hematopoietic stem/progenitor cells

目的 :研究 VLA- 5及 VLA- 6是否参与内皮细胞促进的造血干 /祖细胞定向移行。方法 :对纯化人 CD34+ 细胞进行体外移行及阻断实验 ,观察其穿移覆盖人脐静脉内皮细胞 ( HUVECs)滤膜的能力。应用四色荧光活化流式细胞术 ( FACS)检测 CD34+细胞其粘附分子及趋化因子受体CXCR- 4的表达谱。结果 :基质由来因子 ( SDF) - 1 α介导的动员外周血 ( m PB)及骨髓 ( BM)来源的CD34+ 细胞穿透覆盖 HUVECs滤膜百分率分别为 ( 5 6.6± 2 0 .1 ) %及 ( 1 5 .6± 1 .8) % ,显著高于其穿移未覆盖 HUVECs滤膜的比率。预先对 CD34+ 细胞进行抗 VLA- 5和 /或 VLA- 6中和抗体处理可消除这一促进效应。此外 ,BM来源的 CD34+细胞其穿移覆盖及未覆盖 HUVECs滤膜的能力均显著低于 m PB CD34+细胞 ,两者间穿移能力的差异与其 VLA- 5及 VLA- 6(而非 VLA- 4及趋化因子受体 CXCR- 4)抗原表达水平相关。结论 :VLA- 5和 VLA- 6参与 HUVECs促进 HS/PCs穿移能力。

Role of brahma-related gene 1/brahma-associated factor subunits in neural stem/progenitor cells and related neural developmental disorders

Different fates of neural stem/progenitor cells(NSPCs)and their progeny are determined by the gene regulatory network,where a chromatin-remodeling complex affects synergy with other regulators.Here,we review recent research progress indicating that the BRG1/BRM-associated factor(BAF)complex plays an important role in NSPCs during neural development and neural developmental disorders.Several studies based on animal models have shown that mutations in the BAF complex may cause abnormal neural differentiation,which can also lead to various diseases in humans.We discussed BAF complex subunits and their main characteristics in NSPCs.With advances in studies of human pluripotent stem cells and the feasibility of driving their differentiation into NSPCs,we can now investigate the role of the BAF complex in regulating the balance between self-renewal and differentiation of NSPCs.Considering recent progress in these research areas,we suggest that three approaches should be used in investigations in the near future.Sequencing of whole human exome and genome-wide association studies suggest that mutations in the subunits of the BAF complex are related to neurodevelopmental disorders.More insight into the mechanism of BAF complex regulation in NSPCs during neural cell fate decisions and neurodevelopment may help in exploiting new methods for clinical applications.

Tissue-specific cancer stem/progenitor cells:Therapeutic implications

Surgical resection,chemotherapy,and radiation are the standard therapeutic modalities for treating cancer.These approaches are intended to target the more mature and rapidly dividing cancer cells.However,they spare the relatively quiescent and intrinsically resistant cancer stem cells(CSCs)subpopulation residing within the tumor tissue.Thus,a temporary eradication is achieved and the tumor bulk tends to revert supported by CSCs'resistant features.Based on their unique expression profile,the identification,isolation,and selective targeting of CSCs hold great promise for challenging treatment failure and reducing the risk of cancer recurrence.Yet,targeting CSCs is limited mainly by the irrelevance of the utilized cancer models.A new era of targeted and personalized anti-cancer therapies has been developed with cancer patient-derived organoids(PDOs)as a tool for establishing pre-clinical tumor models.Herein,we discuss the updated and presently available tissue-specific CSC markers in five highly occurring solid tumors.Additionally,we highlight the advantage and relevance of the threedimensional PDOs culture model as a platform for modeling cancer,evaluating the efficacy of CSC-based therapeutics,and predicting drug response in cancer patients.

Is Adipocyte Differentiation the Default Lineage for Mesenchymal Stem/Progenitor Cells after Loss of Mechanical Loading? A Perspective from Space Flight and Model Systems

Mesenchymal stem/progenitor cells (MSC/MPC) are found in many tissues and fluids including bone marrow, adipose tissues, muscle, synovial membranes, synovial fluid, and blood. Such cells from different sources can proliferate and differentiate into different lineages (e.g. osteogenic, chondrogenic and adipogenic) after suitable stimulation. However, details regarding the regulation of MSC/MPC proliferation and differentiation status are still unclear and it is likely that regulation involves both biological and mechanical influences in the different environments. It has been noted that in humans and preclinical animal models that exposure to microgravity/space flight or prolonged bed rest (a surrogate for microgravity) can lead to infiltration of skeletal muscle and bone marrow with fat. Similarly, in preclinical models treated with multiple intramuscular injections of Botulinum Toxin A to induce muscle weakness and atrophy, there is also an infiltration of the muscle with fat. The origins and basis for these fat deposits are largely unknown, but there is a possibility that the altered mechanical and biological environments lead to dysregulation of MSC/MPC and progression to preferential differentiation towards the adipocyte lineage. Furthermore, loss of MSC regulatory control by either mechanical and/or biological factors may also contribute to their involvement in obesity development and progression. Thus, the utility of using MSC/MPC from some sources for tissue engineering purposes may be compromised and further research regarding optimal loading for tissue engineering purposes is likely warranted.